Modi Kushal et al. Int. Res. J. Pharm.

2013, 4 (3)
INTERNATIONAL RESEARCH JOURNAL OF PHARMACY
www.irjponline.com ISSN 2230 – 8407
Review Article

ORAL CONTROLLED RELEASE DRUG DELIVERY SYSTEM: AN OVERVIEW

Modi Kushal1*, Modi Monali2, Mishra Durgavati2, Panchal Mittal2, Sorathiya Umesh3, Shelat Pragna1
1
Department of Pharmaceutics and Pharmaceutical Technology, K. B. Institute of Pharmaceutical Education and Research,
Kadi Sarva Vishwavidyalaya, Gandhinagar, Gujarat, India
2
Department of Pharmaceutical Technology, L. J. Institute of Pharmacy, Ahmadabad, Gujarat, India
3
Department of Pharmaceutics, Indukaka Ipcowala College of Pharmacy, Vithal Udyog nagar, Gujarat, India
Email: kushal.modi@gmail.com

Article Received on: 10/01/13 Revised on: 01/02/13 Approved for publication: 11/03/13

DOI: 10.7897/2230-8407.04312
IRJP is an official publication of Moksha Publishing House. Website: www.mokshaph.com.
© All rights reserved.

ABSTRACT
Oral drug delivery is the most preferred and convenient option as the oral route provides maximum active surface area among all drug delivery system for
administration of various drugs. The attractiveness of these dosage forms is due to awareness to toxicity and ineffectiveness of drugs when administered by
oral conventional method in the form of tablets and capsules. Usually conventional dosage form produces wide range of fluctuation in drug concentration in
the bloodstream and tissues with consequent undesirable toxicity and poor efficiency. The maintenance of concentration of drug in plasma within therapeutic
index is very critical for effective treatment. These factors as well as factors such as repetitive dosing and unpredictable absorption lead to the concept of oral
controlled release drug delivery systems. Controlled release drug delivery system works on many different mechanisms to control the release rate of drugs.
Various mechanisms like osmotic pressure, matrix system, reservoir system, altered density system etc. have been utilized as formulation approaches. The
present article contains brief review on various formulation approaches for controlled release drug delivery system.
Keywords: Controlled release drug delivery system, matrix type system, reservoir system.

INTRODUCTION Advantages of controlled release drug delivery system

Over the Past 30 years, as the expense and complications over the conventional dosage form 4
involved in marketing new drug entities have increased, with · Reduced dosing frequency.
concomitant recognition of the therapeutic advantages of · Dose reduction.
controlled drug delivery, greater attention is being paid on · Improved patient compliance.
development of oral controlled release drug delivery systems. · Constant level of drug concentration in blood plasma.
The goal in designing controlled release drug delivery system · Reduced toxicity due to overdose.
is to reduce the frequency of the dosing, reducing the dose · Reduces the fluctuation of peak valley concentration.
and providing uniform drug delivery. So, controlled release
· Night time dosing can be avoided.
dosage form is a dosage form that releases one or more drugs
continuously in predetermined pattern for a fixed period of
Limitation of Oral Conventional Dosage Form2, 3
time, either systemically or locally to specified target organ 1-
3 1. Poor patient compliance, increased chances of missing the
. Controlled release dosage forms provide better control of
dose of a drug with short half life for which frequent
plasma drug levels, less dosage frequency, less side effect, administration is necessary.
increased efficacy and constant delivery. The modified
2. The unavoidable fluctuations of drug concentration may
release oral delivery system classification is shown in figure
lead to under medication or over medication in narrow
1 3,4 .
therapeutic index drug.
3. A typical peak-valley plasma concentration time profile is
Controlled Release Drug Delivery System
obtained which makes attainment of steady-state condition
Controlled release system means any drug delivery system impossible.
that maintains adequate and desired release of drug over an
extended period of time. Hydrophilic polymer matrix is
Factors affecting the Formulation of Oral controlled
widely used for formulating an controlled dosage form 2-4.
release Drug delivery system
The role of ideal drug delivery system is to provide proper
amount of drug at regular time interval and at right site of
Physicochemical factors
action to maintain therapeutic range of drug in blood plasma.
The IR drug delivery system lacks some features like dose
Aqueous Solubility
maintenance, controlled release rate and site targeting. The Most of the drugs are weak acids or weak bases Drugs with
oral controlled drug delivery has some potential advantage
low water solubility will be difficult to incorporate into
like controlled release rate and dose maintenance in plasma.
sustained release mechanism 2, 5. For a drug with high
The CR formulations have some swelling polymer or waxes
solubility and rapid dissolution rate, it is often quite difficult
or both which controls the release rate. The use of reservoir
to retard its dissolution rate. A drug of high water solubility
system is also well known for controlling release rate. Figure can dissolve in water or gastrointestinal fluid readily and
2 shows the relation between plasma concentration verses
tends to release its dosage form in a burst and thus is
time.
absorbed quickly leading to a sharp increase in the blood
drug concentration compared to less soluble drug. It is often
difficult to incorporate a highly water soluble drug in the

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dosage form and retard the drug release especially when the Biological Factor
dose is high. The pH dependent solubility particularly in the The absorption behaviour of a drug can affect its suitability
physiological pH range would be another problem for as an extended release product. The aim of formulating
controlled release formulation because of the variation in the controlled release product is to place a control on the delivery
pH throughout the gastrointestinal tract and variation in the system 2. It is essential that the rate of release is much slower
dissolution rate. The biopharmaceutical classification system than the rate of absorption. If we assume the transit time of
(BCS) allows estimation of likely contribution of three major dosage forms in the absorptive areas of GI tract is about 8-12
factors solubility, dissolution and intestinal permeability hours, the maximum half-life for absorption should be
which affect the oral absorption. approximately 3-4 hours. Otherwise the dosage form will
Class III (High solubility- Low permeability) and Class IV pass out of absorptive regions before drug release is
(Low solubility- Low permeability) drugs are poor candidates complete. Therefore, the compounds with lower absorption
for controlled release dosage form compound with solubility rate constants are poor candidates. Some possible reasons for
< 0.1 mg/ml face significant solubilisation obstacles and low extent of absorption are poor water solubility, small
often compounds with solubility 10 mg/ml present partition co-efficient, acid hydrolysis and metabolism or its
difficulties to solubilisation dosing formulation. In general, site of absorption. The distribution of drugs in tissues can be
highly soluble drugs are undesirable for formulation in to a important factor in the overall drug elimination kinetics.
controlled release product. Since it not only lowers the concentration of circulating drug
but it also can be rate limiting in its equilibrium with blood
Partition coefficient (P (o/w)) and extra vascular tissue, consequently apparent volume of
Partition coefficient is defined as the fraction of drug in an oil distribution assumes different values depending on time
phase to that of an adjacent aqueous phase. Drugs that passes course of drug disposition. Drugs with high apparent volume
though biological membrane, if partition co-efficient of drug of distribution, which influence the rate of elimination of the
influences shows very much bioavailability because drug are poor candidate for oral CR drug delivery system. For
lipophilic nature of biological membrane. Drugs that have design of sustained release products, formulation scientist
lower partition coefficient are not suitable for oral CR drug must have information on disposition of the drug.
delivery system and drugs that have higher partition co- A drug which extensively metabolizes is not suitable for CR
efficient are also not suitable for oral CR drug delivery drug delivery system. A drug capable of inducing
system because they will not partition out of the lipid metabolism, inhibiting metabolism, metabolized at the site of
membrane once it gets in the membrane 5. absorption or first-pass effect is poor candidate for CR
delivery, as it could be difficult to maintain constant blood
Drug pKa and ionization at physiological pH level. Drugs that are metabolized before absorption, either in
Drugs existing largely in ionized form are poor candidates for lumen or the tissues of the intestine, can show decreased
oral controlled release drug delivery system. Absorption of bioavailability from the controlled releasing systems. Most
the unionized drugs are well whereas permeation of ionized intestinal walls are saturated with enzymes. As drug is
drug is negligible because the absorption rate of ionized drug released at a slow rate to these regions, lesser drug is
is 3-4 times less than that of the unionized drug. The pKa available in the enzyme system. Hence, the systems should be
range for acidic drug whose ionization is pH sensitive is devised so that the drug remains in that environment to allow
around 3.0-7.5 and pKa range for basic drug whose ionization more complete conversion of the drug to its metabolite.
is pH sensitive is around 7.0-11.0 are ideal for optimum
positive absorption. Drug shall be unionized at the site to an Half-life
extent 0.1-5.0% 2. The half-life of a drug is an index of its residence time in the
body. If the drug has short half life (less than 2 hours) the
Drug stability dosage form may contain a prohibitively large quantity of the
Drugs undergo both acid/base hydrolysis and enzymatic drug. On the other hand, drug with elimination half-life of 8
degradation when administered oral route. If the drug in the hours or more are sufficiently controlled in the body, when
solid state the degradation will occur in reduced rate, for the administered in conventional dosage from and controlled
drugs that are unstable in stomach that prolong delivery to the release drug delivery system is generally not necessary in
entire GI tract are beneficial. If drug is administered in such cases. Ideally, the drug should have half-life of 3-4
extended release dosage form that are unstable in small hours for formulation of drug delivery system 2-5.
intestine may demonstrate decreased bioavailability. This
occurs due to the fact that a greater quantity of drug is Therapeutic index
delivered in small intestine and is being subjected to more Drugs with low therapeutic index are unsuitable for
degradation 8-10. incorporation in controlled release formulations. If the system
fails in the body, dose dumping may occur, which leads to
Molecular size and diffusivity toxicity 5.
Diffusivity depends on size and shape of the cavities of the
membrane 7. The diffusion co-efficient of intermediate Size of dose
molecular weight drug is 100-400 Daltons; through flexible If the dose of a drug in the conventional dosage form is high,
polymer range is 10-6-10-9 cm2/sec. For drugs having then it is less suitable candidates for CRDDS. This is because
molecular weight > 500 Daltons, the diffusion coefficient in the size of a unit dose controlled release oral formulation
many polymers are very less i.e. less than 10-12 cm2/sec. The would become too big to administer without difficulty 6.
examples of drugs which are difficult to control release rate
of medicament from dosage form are proteins and peptides. Absorption window
Certain drugs when administered orally are absorbed only
from a specific part of gastrointestinal tract. This part is

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 Modi Kushal et al. Int. Res. J. Pharm. 2013, 4 (3)
referred to as the ‘absorption window’. These candidates are Types of diffusion matrix system
also not suitable for CRDDS 7. The matrix system can be divided into two categories
depending on the types of retarding agents or polymeric
Plasma concentration response relationship materials 11.
Generally, plasma drug concentration is more responsible for · Hydrophobic matrix system
pharmacological activity rather than dose. But the drug · Hydrophilic matrix system
having pharmacological activity independent of plasma · Fat-wax matrix system
concentrations, are poor candidate for oral CR drug delivery Hydrophobic matrix system
system 6. This is the only system where the use of polymer is not
essential to provide controlled drug release, although
Concentration dependency on transfer of drug insoluble polymers can been used. As the term suggests, the
Transfer of drug from one compartment to other, if follows primary rate controlling components of hydrophobic matrix
zero order kinetic process then such drugs are poor candidate are water insoluble in nature. These ingredients include
for oral CR delivery system. It should be of first order waxes glycerides fatty acids, and polymeric materials such as
kinetics7. The figure 3 represents various formulation ethyl cellulose, methyl cellulose and acrylate copolymer. To
strategies for oral controlled release drug delivery system. modulate drug release, it may be necessary to incorporate
soluble ingredients such as lactose into formulation. The
Diffusion Sustained System presence of insoluble ingredient in the formulations helps to
Diffusion process shows the movement of drug molecules maintain the physical dimension of hydrophobic matrix
from a region of a higher concentration to one of lower during drug release. Diffusion of active ingredient from the
concentration. system is the release mechanism and the corresponding
release characteristic can be described by Higuchi equation
Diffusion reservoir system also known as square root of time release kinetic 11.
In this system, a water insoluble polymeric material covers a
core of drug. Drug will partition into the membrane and Hydrophilic matrix system
exchange with the fluid surrounding the particle or tablet. The primary rate limiting ingredients of hydrophilic matrix
Additional drug will enter the polymer, diffuse to the are polymers that would swell when in contact with aqueous
periphery and exchange with the surrounding media. The solution and form a gel layer on the surface of the system 18-
drug release takes place by diffusion mechanism. The 20
. When the release medium is thermodynamically
diffusion type reservoir system is shown in figure 4. compatible with a polymer, the solvent penetrates into the
Advantages free spaces between macromolecular chains. The polymer
· Zero order delivery is possible. may undergo a relaxation process due to the stress of the
· Release rates can be modified with polymer type and penetrated solvent, so that the polymer chains become more
concentration. flexible and the matrix swells. This allows the encapsulated
Disadvantages drug to diffuse more rapidly out of the matrix. On the other
· Difficult to deliver high molecular weight compound. hand, it would take more time for drug to diffuse out of the
· Generally increased cost per dosage unit. matrix since matrix swelling lengthens the diffusion path. It
· Potential toxicity if dose dumping occurs. has been widely known that swelling and diffusion are not
the only factors that determine the rate of drug release. For
Diffusion matrix system dissolvable polymer matrix, polymer dissolution is another
The matrix system is defined as a well-mixed composite of important mechanism that can modulate the drug delivery
one or more drugs with gelling agent i.e. hydrophilic rate. While either swelling or dissolution can be the
polymers. Matrix systems are widely used for sustaining the predominant factor for a specific type of polymers, in most
release rate. It is the release system which prolongs and cases drug release kinetics is a result of a combination of
controls the release of the drug that is dissolved or dispersed these two mechanisms. The presence of water decreases the
7, 18 glass transition temperature (Tg) (for HPMC from 184°C to
. A solid drug is dispersed in an insoluble matrix and the
rate of release of drug is dependent on the rate of drug below 37°C), giving rise to transformation of glassy polymer
diffusion and not on the rate of solid dissolution. The to rubbery phase (gel layer). The enhanced motility of the
diffusion type matrix system is shown in figure 5. polymeric chain favors the transport of dissolved drug.
Advantages Polymer relaxation phenomena determine the swelling or
· Easier to produce than reservoir or encapsulated devices. volume increase of the matrix. The main polymers used in
· Versatile, effective and low cost. hydrophilic matrices are hydroxy propyl methyl cellulose
· Possible to formulate high molecular weight compounds. (HPMC) and Hydroxy propyl cellulose (HPC), Xanthan gum,
· Increased the stability by protecting the drug from Carbopol and Alginates.
hydrolysis or other derivative changes in gastrointestinal
tract. Fat-Wax matrix tablet
Disadvantages The drug can be incorporated into fat wax granulations by
· The ghost matrix must be removed after the drug has been spray congealing in air, blend congealing in an aqueous
released. media with or without the aid of surfactant and spray-drying
techniques 12, 13. In the bulk congealing method, a suspension
· The release rates are affected by various factors such as,
of drug and melted fat-wax is allowed to solidify and is then
food and the rate transit through the gut.
comminuted for sustained release granulations. The mixture
· Cannot provide pure zero order release.
of active ingredients, waxy materials and fillers also can be
converted into granules by compacting with roller compactor,
heating in a suitable mixture such as fluidized-bed and steam
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jacketed blender or granulating with a solution of waxy polymer as stand alone or in combination with different
material or other binders. The drug embedded into a melt of polymers for release rate control.
fats and waxes is released by leaching and/ or hydrolysis as
well as dissolution of fats under the influence of enzymes and Ion Exchange Resins Controlled Release
pH change in the gastrointestinal tract. The addition of Ion exchange resins are cross-linked water-insoluble
surfactants to the formulation can also influence both the polymers carrying ionisable functional groups 27. The resins
drug release rate and the proportion of total drug that can be have been used in various pharmaceutical applications,
incorporated into a matrix. primarily for taste masking and controlled release systems. In
tablet formulations, ion exchange resins have been used as
Dissolution Controlled Systems disintegrant, because of their swelling ability. It forms
A drug with a slow dissolution rate is inherently sustained irreversible complex with ionisable drugs upon prolonged
and for those drugs with high water solubility, one can exposure of the drug to the resin. A resin bound drug is
decrease dissolution through appropriate salt or derivative removed when appropriate ions are in contact with ion-
formation13, 14. These systems are most commonly employed exchanged groups. The area and length of diffusion pathway
in the production of enteric coated dosage forms. To protect and the amount of cross-linked polymer in the resin moiety
the stomach from the effects of drugs such as Aspirin, a governs the rate of drug release. Sriwongjanya et al. has
coating that dissolves in natural or alkaline media is used. found the effect of ion exchange resin with drug containing
This inhibits release of drug from the dosage form until it opposite charge in matrix system. After this investigation
reaches the higher pH of the intestine. In most cases, enteric they concluded that the release of drug containing opposite
coated dosage forms are not truly sustaining in nature, but charge retarded by the addition of ion exchange resin to
serve as a useful function in directing release of the drug to a HPMC-matrices due to formation of complex between drug
special site. The same approach can be employed for and resin.
compounds that are degraded by the harsh conditions found
in the gastric region. Methods using Osmotic Pressure
In this method, the release controlling factor that must be
Soluble reservoir system optimized is the osmotic pressure gradient between inside the
In this system drug is coated with a given thickness coating, compartment and the external environment 28, 29. The simplest
which is slowly dissolved in the contents of gastrointestinal and most predictable way to achieve a constant osmotic
tract by alternating layers of drug with the rate controlling pressure is to maintain a saturated solution of osmotic agent
coats as shown in figure 6. A pulsed delivery can be in the compartment. This technology provides zero order
achieved, if the outer layer is quickly releasing bolus dose of release used for hydrophilic drugs. Drug may be osmotically
the drug, initial levels of the drug in the body can be quickly active or combine with osmotically active salt eg. NaCl.
established with pulsed intervals. This is not a true sustained Osmotic pressure is the hydrostatic pressure produced by a
release system; the biological effects can be similar. An solution in a space divided by a semi permeable membrane
alternative method is to administer the drug as group of beads due to difference in concentration of solutes. Osmosis is the
that have coating of different thickness. diffusion of fluid through a semi permeable membrane from a
Since the beads have different coating thickness, their release solution with a low solute concentration to a solution with a
occurs in a progressive manner. Those with the thinnest higher solute concentration until there is an equal
layers will provide the initial dose. The maintenance dose of concentration of fluid on both sides of the membrane. A semi
drug can be achieved by applying thicker coating. This is the permeable membrane is placed around a tablet, particle or
principle of the spansule capsule. Cellulose nitrate phthalate drug solution that allows transport of water into the tablet
was synthesized and used as an enteric coating agent for with eventual pumping of drug solution out of the tablet
acetyl salicylic acid tablets. through a small delivery aperture in tablet coating. The
osmotic systems are classified in major two types, i.e. type-A
Soluble matrix system and type-B. In type-A system, the core contains both, the
It can be either a drug impregnated sphere or a drug drug and electrolytes. The electrolytes provide osmotic
impregnated tablet, which will be subjected to slow erosion pressure and maintain the rate of drug release. In type-B
14, 15
. The more common type of dissolution sustained dosage system, the drug solution is present in a semi permeable
form is shown in figure 7. membrane surrounded by the electrolytes. Both the systems
are shown in figure 8 and 9 respectively.
Dissolution- sustained pulsed delivery systems The OCODDS can be conveniently classified in to following
Amongst controlled release formulations hydrophilic matrix types: 22-24
technology is the most widely used due to its following
advantages 16, 17. Single chamber osmotic pump
· Provide desired release profile for a wide therapeutic drug · Elementary osmotic pump (EOP)
category, drug and solubility.
· Simple and cost effective manufacturing and robust. Multi chamber osmotic pump
· Patient acceptance. · Push pull osmotic pump.
· Ease of drug modulation through level, choice of · Osmotic pump with non expanding second chamber.
polymeric systems and function coating.
A hydrophilic matrix tablet consists of mixture of drug, Specific types
polymer and excipients (filler/diluents as well as other · Controlled porosity osmotic pump.
excipients) prepared by hydrophilic polymer in the matrix. · Monolithic osmotic systems.
Formulators often choose from a range of hydrophilic · Osmotic bursting osmotic pump.

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· OROS – CT the formulation to help to maintain a constant pH thereby
· Multi particulate delayed release systems (MPDRS) rendering pH independent drug release 25, 26. A buffered
· Liquid Oral Osmotic System (L-OROS) formulation is prepared by mixing a basic or acidic drug with
one or more buffering agent, granulating with appropriate
pH Independent Formulations pharmaceutical excipients and coating with gastrointestinal
Most drugs are either weak acids or weak bases. The release fluid permeable film forming polymer. When gastrointestinal
from controlled release formulations is pH dependent. fluid permeates through the membrane, the buffering agents
However; buffers such as salts of amino acids, citric acid, adjust the fluid inside to suitable constant pH thereby
phthalic acid phosphoric acid or tartaric acid can be added to rendering a constant rate of drug release.

Table 1: Marketed drug products with their mechanism based classification

SN Technology Brand name Drug Manufacturer

1. Diffusion controlled release Welbutrin XL Bupropion GlaxoSmithKline
2. Matrix system tablet Ambien CR Zolpidem Tartarate Sanofi-Aventis
3. Method using ion Exchange Tussionex Pennkinetic Hydrocodone Polistirex and UCB Inc.
ER suspension Chlorpheneramine Polistirex
4. Methods using Elementary Osmotic Pump Efidac 24® Chlorpheniramine Maleate Novartis
Osmotic pressure Push-Pull Osmotic Systems Glucotrol XL® Glipizide Pfizer Inc.
5. pH independent formulation Inderal® LA Propranolol HCl Wyeth Inc.
6. Altered density formulation Modapar Levodopa and Benserazide Roche Products, USA

Figure 1: Classification of modified release drug delivery system

Figure 2: Ideal plasma concentration curves for immediate release, Zero order release, sustained release drug delivery system

Figure 3: formulation strategy for oral controlled release drug delivery system

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 Modi Kushal et al. Int. Res. J. Pharm. 2013, 4 (3)

Figure 4: Schematic representation of diffusion type reservoir system Figure 5: Schematic representation of diffusion type matrix system

Figure 6: Schematic representation of dissolution of reservoir system Figure 7: Schematic representation of dissolution matrix system

Figure 8: Type-A osmotic system

Figure 9: Type-B osmotic system

Altered Density Formulations From the above discussion, we can concluded that the
Several approaches have been developed to prolong the controlled release drug delivery system is very helpful in
residence time of drug delivery system in the gastrointestinal increasing the efficiency of the dose as well as the patient
tract 21, 22. The delivery system remains in the vicinity of the compliance. Moreover; the reasonable cost of oral controlled
absorption site until most, if not all of its drug contents is release drug delivery system has lead ease of market
released. In high density approach, the density of the pellets penetration as replacement of oral conventional drug delivery
must exceed that of normal stomach content and should system.
therefore be at least 1-4g/cm3. In low density approach, the
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19. Sung KC, Nixon PR, Skoug JW. Effect of formulation variables on drug Modi Kushal, Modi Monali, Mishra Durgavati, Panchal Mittal, Sorathiya
and polymer release from HPMC-based matrix tablets. Int. J. Pharm. Umesh, Shelat Pragna. Oral controlled release drug delivery system: An
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Source of support: Nil, Conflict of interest: None Declared

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 Development and Evaluation of Colon Targeted Drug
Delivery System by Using Natural Polysaccharides/Polymers
G.R. Godge1 and S.N. Hiremath2
1
P.D.V.V.P.F’S College of Pharmacy, Vilad Ghat, Ahmednagar-414111, India
2
PRES’S College of Pharmacy, a/p Chincholi, Sinnar, Nashik-422101, India

Received: September 05, 2013; Accepted: November 20, 2013; Published (web): June 29, 2014

ABSTRACT: Colon is being extensively investigated as a drug delivery site. This study contains comparison of the
usual enteric coating polymers viz. xanthan gum, guar gum, chitosan and ethyl cellulose, as carriers for colon specific
drug delivery. Lactose based metoprolol succinate tablets were prepared. These were coated with one of the coating
polymers to a varying coat thickness. Tablets were prepared using polysaccharides or synthetic polymer as binders.
These included xanthan gum, guar gum, chitosan and ethyl cellulose. Metoprolol Succinate was used as a model
drug. The prepared tablets were enteric coated with kollicoat MAE 100 DP to give protection in the stomach. The
coated tablets were tested in-vitro for their suitability as colon specific drug delivery systems. The drug release
studies were carried out in simulated stomach environment (pH 1.2) for 2 h followed by small intestinal environment
at pH 6.8. The dissolution data obtained from tablets demonstrates that the dissolution rate of the tablet is dependent
upon the type and concentration of polysaccharide/polymer used as binder. The results demonstrate that enteric
coated tablets containing 3% chitosan as a binder, showed only 12.5% drug release in the first 5 h, which is the usual
upper gastrointestinal transit time, whereas, tablets prepared using guar gum as binder, were unable to protect drug
release under similar conditions. Preparations with xanthan gum as a binder formed time-dependent release
formulations. When used in a concentration of 5.92% in the tablets, 28% drug release was observed in the usual
upper gastrointestinal tract conditions. It was also found that enteric coated preparation formulated with 8.88% of
kollicoat MAE 100 DP as binder could be used to carry water insoluble drug molecules. The above study shows that
chitosan could be successfully used as a binder, for colon targeting of water insoluble drugs in preference to guar
gum when used in the same concentration. Additionally, formulations developed with chitosan and kollicoat MAE
100 DP would be highly site specific since drug release would be at a retarded rate till microbial degradation or
polymer solubilization takes place in the colon.
Key words: Enteric coating, shellac, colon specific drug delivery, colon targeting, solubilizsation.

INTRODUCTION
Colonic drug delivery has gained increased enzymes for polysaccharides (e.g., β-D-glucosidase,
importance not just for the delivery of drugs for the β-D-galactosidase, amylase, pectinase, xylase,
treatment of local diseases of colon such as irritable dextranase, etc.) which were secreted by a large
bowel syndrome, inflammatory bowel disease (IBD) number and variety of colonic bacteria.3,4 Most of the
including Crohn’s disease and ulcerative colitis but systems which have been developed for colon-
also for its potential for the delivery of proteins and specific drug delivery till date includes coating with
therapeutic peptides like insulin.1,2 Recently colon pH-sensitive polymers, covalent linkage of a drug
has emerged as a potential site which offers distinct with a carrier, time dependent release systems, and
advantages on account of a near neutral pH, a much enzymatically controlled delivery systems.5 Enteric
longer transit time, reduced digestive enzymatic coated systems, though they are the most commonly
activity, much greater response to absorption used for colonic drug delivery systems do not allow
enhancers, and the presence of large amounts of reproducible drug release. The disadvantage of this
Correspondence to: G.R. Godge system is that the pH difference between small
Ph: +919028757508, Fax: 0241-2778044 intestine and colon is not being very pronounced.
E-mail: grgodge@yahoo.com
Moreover, the limitation of time dependent release
Dhaka Univ. J. Pharm. Sci. 13(1): 105-113, 2014 (June) system is that it is not able to sense any variation in
106 Godge and Hiremath

the upper gastro-intestinal tract transit time, any prevent drug release in the stomach and had an
variation in gastric emptying time may lead to drug additional lag phase in the formulation to retard drug
release in small intestine before arrival to colon. release in the small intestine. Although enteric coated
Therefore, the most convenient approach known for systems with such lag phases have been developed
site-specific drug delivery to colon is enzymatically earlier, but being relatively complex systems, their
controlled delivery systems. No drug release can large scale manufacturing requires a lot of
occur unless the system arrives to the colon.6 Many technological advancement and skills.12,13 So, an
protein and peptide drugs like insulin, cannot be attempt was made to formulate a dosage form, which
administered through the oral route because of their could be formulated easily, using the usual tableting
degradation by the digestive enzymes of the stomach techniques and usual tableting ingredients, with little
and the small intestine. To improve the specificity of modification in the method of processing of the
drug release, certain types of neutral polysaccharides ingredients.
(e.g., pectin, xanthin gum chitosan, dextran, guar
gum, and inulin) can be used to create the MATERIALS AND METHODS
enzymatically controlled delivery systems. To reach
Metoprolol succinate was a generous gift from
the colon and to be able to specifically deliver a
Cadila Healthcare Pvt. Limited (Ahmadabad) India.
peptide or a protein drug, the dosage form must be
Guar gum, xanthin gum, ethyl cellulose and chitosan
formulated taking into account the obstacles of upper
(degree of deacetylation >85%), were obtained as gift
gastro-intestinal tract and advantages of colonic
samples from Rajesh Chemicals, Mumbai, India.
environment.7,8 Polysaccharides can be easily
Kollicoat MAE 100 DP was obtained as gift sample
modified chemically and biochemically and are
from BASF Mumbai. All other ingredients used in
highly stable, safe, nontoxic, hydrophilic and gel
the preparation and coating of tablets were of
forming and in addition biodegradable, which
analytical grade.
suggests their use in targeted drug delivery systems.
Preparation of matrix tablets. Matrix tablets
They are polymers of monosaccharide’s (sugars).
using metoprolol succinate and natural
They are found in abundance, have wide availability,
polysaccharides were prepared with proper selection
and are inexpensive and available in a variety of
of excipients.Various excipients used during
structures with a variety of properties.9 Metoprolol
preparation of matrix tablet are Avicel pH 112,
succinate is a selective β1 receptor blocker used in
directly compressible lactose, microcrystalline
treatment of several diseases of the cardiovascular
cellulose, magnesium stearate and talc etc. Binder
system, especially hypertension. Metoprolol is used
solution of various natural polysaccharides were
for a number of conditions including: hypertension,
prepared as per desired concentration as shown in
angina, acute myocardial infarction, supraventricular
Table no.1. and granules so prepared using active
tachycardia, ventricular tachycardia, congestive heart
ingredient were dried in oven at 40°C.
failure, and prevention of migraine headaches10. It is
freely insoluble in water, freely soluble in acetone, Preparation of granules. All the powdered
soluble in alcohol. Metoprolol undergoes a- ingredients were weighed, mixed and granulated with
hydroxylation and O-demethylation as a substrate of the binder solution/ paste prepared as above. This
the cytochrome liver enzymes CYP2D611 and a small mixture was thoroughly blended manually and passed
percentage by CYP3A4. It is selective, moderately through a sieve with a nominal aperture of 1 mm. The
lipophilic drug without intrinsic sympathomimetic granules prepared were dried in a tray drier at a
activity (ISA). Due to its short half-life, therefore temperature between 30 and 40°C for 4 h. The dried
must be taken at least twice daily or as a slow-release granules were screened, mixed with lubricants and
preparation. The purpose of this study was to stored for tableting.
formulate a dosage form which was enteric coated to
Development and Evaluation of Colon Targeted Drug 107

Preparation of core tablets. Tablets weighing 400 (1.25% w/w) was used as a plasticizer. The
200 mg containing 100 mg of metoprolol succinate percent weight increase of each batch of tablet after
were individually punched on a rotary punch coating varied between 2.9 ± 0.04% w/w.
tableting machine (CAP Works, Ahmedabad, India) Swelling studies. Uncoated tablets containing
using concave die-punch. The tablets had hardness xanthan gum and guar gum as binder in varying
between 5 and 7 kg/cm2. Various in process quality concentrations were subjected to swelling studies 14,15
control tests were performed on the prepared tablets at a temperature of 370C and at a pH of 6.8, using the
viz., content uniformity, hardness, friability, same buffer that was used for dissolution studies.
disintegration, etc. Swelling studies were conducted in triplicate for each
Coating of core tablet. Each batch of the tablet binder concentration. Manually radial swelling of
was coated with a 12.5% w/v solution of Kollicoat tablet width was noted, from time to time (Figs. 1 and
MAE 100 DP, using a pan coating equipment. PEG- 2).

Fig. 1 Swelling index vs. time graph of XG tablets at 6.8 pH (370 C)

Fig.2 Swelling index vs. time graph of GG tablets at 6.8 pH (370 C)

108 Godge and Hiremath

Drug release studies. The capability of the in 24 h. Upon increasing the concentration of XG
prepared tablets to retard drug release in the from 2.96% (XG5) to 4.44% (XG7), the initial
physiological environment of the GIT was assessed amount of drug release was decreased, showing 22%
by conducting drug release studies in simulated release in the next 3 h but the total amount of drug
stomach and small intestinal pH, respectively. The release in 24 h was increased to 82%. Further,
changing pH media, Method 1, USP 23, for delayed increase in concentration of xanthan gum to 5.92%
release tablets was used. Dissolution test was (XG10), though, initially drug release was moderate,
conducted in USP 1 apparatus at 75 rpm and a but this was followed by a rapid drug release and
temperature of 370C. Initial drug release studies were nearly 100% drug was released in 18 h.
conducted in 750 ml of 0.1N HCl for 2 h. Then, 250 The rate of drug release which was found to be
ml of 0.2 M trisodium phosphate was added to the decreased initially (Fig. 3) upon increasing the
dissolution media and the pH adjusted to 6.8. Drug concentration of xanthan gum can be explained on
release studies were conducted in triplicate for each the basis that a higher binder concentration led to an
polymer/binder concentration. Manually samples increase in hardness of the tablet, while the porosity
were withdrawn after regular intervals of time to and capillary pore sizes were reduced16. This in-turn
evaluate drug release and sink condition were reduced the wicking of water into the tablet and
maintained. These were analyzed spectrophoto- consequently the swelling and drug release rates are
metrically at a wavelength of 230.2 nm. slowed.
The release of the drug by a matrix system is
RESULTS AND DISCUSSION generally produced by two simultaneous
For the formulation of a delivery system mechanisms: (a) attrition or erosion of the outermost,
targeting colon, it is an essential prerequisite that the least consistent gel layer, (b) dissolution of the drug
drug release should be minimal until the dosage form (active principle) in the liquid medium and diffusion
reaches the colon. The normal transit time in the through the gel barrier when formed. These tablets
stomach is 2 h (though this may vary). The transit showed a considerable swelling at a pH of 6.8
time in small intestine is relatively constant and is (Fig. 1) and the drug was dispersed in the swollen
3 h. So, after gastric emptying, the drug release from matrix formed by the polysaccharide.17-19
the dosage form is to be retarded during transit Past studies carried out on swellable matrices
through the small intestine (3 h). To overcome the have shown that as the concentration of the swellable
variation in transit time of stomach the tablets polymer is increased in the formulation, the gel
prepared were enteric coated. None of the tablets thickness increases upon swelling. Due to this it
showed drug release during the first 2 h in 0.1N HCl. increases the diffusion path length, which in turn
When the pH was changed to 6.8, enteric layer decreases the drug release from the tablet14.
dissolved and further drug release rate was dependent However, in the present study though, upon
upon the type and concentration of binder used in the increasing the polysaccharide concentration, the
tablets. swelling increased, but after a certain lag phase, the
Xanthan gum as binder. Studies indicated that drug release was increased rather than being
XG tablets did not show any drug release during the decreased, which is normally observed from a matrix
initial 2 h in the acidic media due to the enteric tablet. This can be explained on the basis that these
coating but when the pH was changed to 6.8, drug tablets upon swelling form rather loose gels due to a
release started, but was found at a retarded rate. The very low concentration of the polysaccharide. Since
percent drug release from XG5 tablets in the next 3 h the release of drug from these matrices takes place by
was 24% and a total of 70% of the drug was released polysaccharide attrition/erosion, which further
depends upon the gel consistency20. As gel becomes
Development and Evaluation of Colon Targeted Drug 109

looser, the matrix becomes more susceptible to release. Studies indicated that time-controlled release
erosion and hence faster is the drug release. This systems for colon targeting can be formulated using
accounts for the drug release behavior in case of XG XG as a binder which initially retards drug release
tablets. Hence, after an initial lag phase (time taken due to the lag time required for swelling and after
by the matrix to swell) increase in concentration of swelling, a rapid drug release was obtained.
binder in XG tablets increases swelling and drug
Table 1 Quantity of binder in gm for 75 tablets

Serial Formulation Xanthin Guar Chitosan Ethyl cellulose Percentage of binder

number code gum gum
1. XG5 0.500 -- -- -- 2.96
2. XG7 0.750 -- -- -- 4.44
3. XG10 1.00 -- -- -- 5.92
4. GG3 -- 0.300 -- -- 1.77
5. GG4 -- 0.400 -- -- 2.37
6. GG5 -- 0.500 -- -- 2.96
7. CH3 -- -- 0.300 -- 1.77
8. CH4 -- -- 0.400 -- 2.37
9. CH5 -- -- 0.500 -- 2.96
10. EC5 -- -- -- 0.500 2.96
11. EC7 -- -- -- 0.750 4.44
12. EC10 -- -- -- 1.00 5.92
13. EC15 -- -- -- 1.5 8.88

Table 2 Cumulative percent drug release from the tablets at varying time intervals (n= 3)

Sl..No. Tablet code Percent drug release Percent drug release Percent drug release
(2 h) (5 h) (24 h)
1. XG5 0 24 70
2. XG7 0 22 82
3. XG10 0 25 100
4. GG3 0 68 100
5. GG4 0 55 100
6. GG5 0 49 100
7. CH3 0 16 73
8. CH4 0 13 61
9. CH5 0 11 49
10. EC5 0 83 100
11. EC7 0 29 97
12. EC10 0 25 84
13. EC15 0 19 59

Guar gum as a binder. GG tablets shown a drug release versus time graph shows that as much as
rather rapid drug release after second hour of 68, 55 and 49% drug release was observed in the first
dissolution showing that as the enteric layer 5 h of dissolution of GG3, GG4 and GG5 tablets,
dissolved, the gum used as a binder could not respectively (Fig. 4). Complete drug was released
effectively retard drug release. In GG3 tablets with a from the tablets at around 20th h. Upon increase in
concentration of 1.77% of gum, drug release could concentration of gum in GG tablets increase in
not be retarded. Increasing the concentration of guar swelling index (Fig. 2) was observed even though the
gum in the tablet from 1.77 to 2.37% and then to drug release was not much affected and no optimum
2.96% did retard the drug release profile further but a lag time was achieved as required to bypass the drug
significant reduction was not observed. The percent release in upper parts of GIT. This may be due to the
110 Godge and Hiremath

concentration of the gum present was not sufficient to formulation from 1.77 to 2.37% in CH4, and then to
retard the drug release, and also lower swelling of 2.96% in CH5 tablets further retarded drug release
guar gum tablets. from the dosage form. Percent drug release at 5 h was
Chitosan as a binder. The cumulative percent reduced to 13% in CH4 tablets and further to 11% in
drug release versus time profile for CH as binder CH5 tablets. The total amount of drug released from
showed that at a concentration of 1.77% (in CH3 CH3, CH4, and CH5 tablets was around 73%, 61%
tablets), the drug release in the initial 5 h was 16%. and 49%, respectively in 24 h (Fig. 5, Table 2).
Increasing the concentration of chitosan in the
% Drug Release

Time (h)
Fig. 3 Percent drug release vs. time graph of XG tablets.
% Drug Release

Time (h)

Fig. 4 Percent drug release vs. time graph of GG tablets

This remarkable decrease in release rate after These tablets formulated using chitosan did not show
increasing the concentration of chitosan can be any swelling in basic environments, so drug release
explained on the basis that as the concentration of due to swelling & polymer erosion was found to be
binder in the system is increased, capillary sizes, minimized. This explains why the rate of drug release
hardness & porosity are reduced. Hence, it reduces was not as high as in the case of other swellable
the wicking of water into the tablet, which decreases gums.
the disintegration and in-turn dissolution processes.
Development and Evaluation of Colon Targeted Drug 111

Thus, systems formulated using chitosan as a Similarly once these CH tablets reach the colon,
binder have been found to protect majority of drug chitosan shall be broken down by the microflora of
release during the usual upper GIT transit time of 5 h. the colon and the total amount of drug shall be
However, there have been a number of reports where released from the dosage form. These tablets can also
chitosan has been found to be digested by the tolerate variation in upper GIT transit time, since the
microflora of the colon. Enteric-coated chitosan rate of drug release before arrival into the colon
capsules have been known to be site specific for the remain retarded. These tablets seem to be highly site
colonic delivery of drug molecules, since they release specific because drug shall be released only upon
the drug upon bacterial degradation in the colon.21,22 specific bacterial degradation of the binding agent i.e.
chitosan in the colon.
% Drug Release

Time (h)
Fig. 5 Percent drug release vs. time graph of CH tablets.
% Drug Release

Time (h)

Fig. 6 Percent drug release vs. time graph of EC tablets.

112 Godge and Hiremath

Ethyl cellulose as binder. Studies indicated that formulated using chitosan as binders seems to be
enteric coated system with EC as binders protected highly site specific due to release of majority of drug
drug release for an initial 2 h in acidic media. In the only upon breakdown by the bacterial microflora of
alkaline environment (pH 6.8) the enteric layer the colon. These formulations could act as colon
dissolves, and EC, being soluble only at lower pH specific drug delivery systems using as low as 2.96%
values (lower than 5) finds an unfavourable of chitosan as binders. Such a low concentration of
environment for dissolution and thereby drug release chitosan has shown high site specificity. An
was retarded (Fig. 6). However, a concentration of additional advantage of these systems is that they
2.96% (i.e. in EC5 tablets) was not able to protect could be formulated easily with reliable practicable
drug release from the tablets and a sharp increase in method, using the usual tableting and coating
drug release was observed with-in the next 1 h and techniques. Systems formulated using upto 2.96% of
83% of drug release was observed in the next 3 h. guar gum could not carry the drug to the colon and
Upon increasing the concentration of the binder EC found to release their contents in early hours of their
in the tablet to 4.44% (EC7 tablets) the drug release administration. Systems formulated with 8.88% of
during the first 5 h of dissolution was retarded ethyl cellulose as binders could be used to deliver
showing percent drug release of around 29% as water soluble drugs site-specifically to the colon in
against 80% in EC5 tablets. Further increase in chronological disorders.
concentration of binder to 5.92 and then to 8.88% in
EC 10 and EE 15 tablets, reduced percent drug ACKNOWLEDGEMENTS
release in first 5 h to 25% and 19%, respectively. The The authors are thankful to principal of
total amount of drug released in 24 h reduced from P.D.V.V.P. Foundation' College of Pharmacy,
100 to 97% followed by 84 and then 59% in EC5, Ahmednagar, Maharashtra for providing necessary
EC7, EC10 and EC15 tablets, respectively (Table 2). facilities without which this work could not possible.
Upon increasing the concentration of binder this Authors are also thankful to Mrs. B.G. Godge for
reduction in rate of drug release can be explained on providing necessary technical assistance.
the assumption that after drying of granules a film is
formed by the binder over the granules.23,24
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DOI: 10.1208/s12249-015-0350-9

Review Article

Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches

Seth Amidon,1 Jack E. Brown,1 and Vivek S. Dave1,2

Received 3 February 2015; accepted 4 June 2015; published online 13 June 2015

Abstract. Colon-specific drug delivery systems (CDDS) are desirable for the treatment of a range of local
diseases such as ulcerative colitis, Crohn’s disease, irritable bowel syndrome, chronic pancreatitis, and
colonic cancer. In addition, the colon can be a potential site for the systemic absorption of several drugs to
treat non-colonic conditions. Drugs such as proteins and peptides that are known to degrade in the
extreme gastric pH, if delivered to the colon intact, can be systemically absorbed by colonic mucosa. In
order to achieve effective therapeutic outcomes, it is imperative that the designed delivery system
specifically targets the drugs into the colon. Several formulation approaches have been explored in the
development colon-targeted drug delivery systems. These approaches involve the use of formulation
components that interact with one or more aspects of gastrointestinal (GI) physiology, such as the
difference in the pH along the GI tract, the presence of colonic microflora, and enzymes, to achieve colon
targeting. This article highlights the factors influencing colon-specific drug delivery and colonic bioavail-
ability, and the limitations associated with CDDS. Further, the review provides a systematic discussion of
various conventional, as well as relatively newer formulation approaches/technologies currently being
utilized for the development of CDDS.
KEY WORDS: colon targeting; factors affecting colon delivery; future trends; novel approaches;
traditional approaches.

INTRODUCTION require sterile preparation (2). Direct rectal delivery of drugs

is challenging with respect to targeting a drug to specific sites
Colon-targeted drug delivery has been the focus of nu- within the colon (2,4). Additionally, the extent of drug distri-
merous studies in recent years due to its potential to improve bution varies for different rectal dosage forms depending on
treatment of local diseases affecting the colon, while minimiz- their spreading capacity and retention time.
ing systemic side effects. Some examples of disease states The success of a colon-specific drug delivery system
which impact the colon include Crohn’s disease (CD), ulcera- (CDDS) depends on the drug’s physico-chemical properties,
tive colitis (UC), and irritable bowel syndrome (IBS) (1). the type of delivery system, all other factors which may influ-
Some of the frequently used drugs for the treatment of these ence the GI transit time, as well as the degree of interaction
ailments include sulfasalazine, dexamethasone, hydrocorti- between the drug and the GI tract (1). It is essential for oral
sone, metronidazole, prednisolone, and others (2). CDDS to protect the drug from being released in the stomach
The delivery of these drugs specifically to the colon with- and small intestine (4). Thus, the approaches used in develop-
out being absorbed first in the upper gastrointestinal (GI) ing a CDDS are aimed at delaying the drug release until the
tract allows for a higher concentration of the drug to reach system reaches the colon, with some strategies demonstrating
the colon with minimal systemic absorption (3). The colonic better success than others. Several marketed formulations
contents have a longer retention time (up to 5 days), and the report the use of a combination of conventional and newer
colonic mucosa is known to facilitate the absorption of several approaches discussed above (Table I).
drugs, making this organ an ideal site for drug delivery (3,4).
A drug can be delivered to the colon via the oral, or the rectal
route. Oral dosage forms are the most preferred delivery DRUG CRITERIA FOR A COLON-SPECIFIC DELI
route for colon-specific delivery due to their convenience VERY
(4). Oral dosage forms also allow for a greater degree of
flexibility in their manufacturing, design, improved patient Drugs which are meant to be incorporated into a colon-
adherence, relatively safe administration, and they do not specific delivery system should fulfill one or more of the
following physico-chemical/therapeutic criteria (1,4). First,
these drugs should exhibit local effects in the colon to treat
1
Wegmans School of Pharmacy, St. John Fisher College, 3690 East intestinal diseases. Peptide drugs like amylin and non-peptide
Avenue, Rochester, New York 14618, USA. drugs such as oxyprenolol are some examples of agents with
2
To whom correspondence should be addressed. (e-mail: these effects. Secondly, these drugs may demonstrate a sub-
viveksdave@gmail.com) optimal absorption in the upper gastrointestinal tract. This

731 1530-9932/15/0400-0731/0 # 2015 American Association of Pharmaceutical Scientists

732 Amidon et al.

Table I. Currently Marketed Formulations

Colon disease/disorder Drugs Delivery system

Inflammatory bowel disease Mesalazine

Ulcerative colitis - Asacol® DR tablets
Crohn’s disease - Pentasa® TR capsules
Sulfasalazine
- Azulfidine EN-tabs® DR tablets
Prednisone
- Rayos® DR tablets
Budesonide
-MMX® Multi-matrix tablets
- Uceris® ER tablets
- Clipper® Gastro-resistant prolonged-release tablets
Prednisolone (Colal-Pred®) Oral colon-targeted pellets
Metronidazole (Flagyl® ER) ER tablets
Azathioprine (Azasan®) IR tablets
Mercaptopurine (Purinethol®) IR tablets
Cyclosporine (Gengraf®) IR capsules, oral solution
Diverticulosis and diverticulitis Methylcellulose (Citrucel®) Oral powder, IR tablet
Psyllium (Metamucil®) Oral powder, IR capsule
Mesalazine (Asacol®) DR tablets
Rifaximin (Xifaxan®) IR tablets
Colonic amoebiasis Doxycycline (Doryx®) DR tablets
Metronidazole (Flagyl® ER) ER tablets
Irritable bowel syndrome Methylcellulose (Citrucel®) Oral powder, IR tablets
Psyllium (Metamucil®) Oral powder, IR capsules
Loperamide (Imodium®) IR capsules
Dicyclomine (Bentyl®) IR capsules, IR tablets
Hyoscyamine (Levbid®) ER tablets
Lubiprostone (Amitiza®) Soft gelatin IR capsule
Linaclotide (Linzess®) IR capsules
Rifaximin (Xifaxan®) IR tablets
Amitriptyline (Elavil®) IR tablets

IR immediate release, ER extended release, DR delayed release, TR timed release

includes antianginal drugs such as isosorbide dinitrate. the colonic content e.g., dietary residues, intestinal secretions,
Agents used in the treatment of colon or rectal cancers mucus, or fecal matter can have a negative influence on the
(e.g., 5-flurouracil and capecitabine) are also ideal candi- stability of the drug (5). In addition, the colonic bacterial enzymes
dates for CDDS. The remaining criteria include a high may also degrade the drug, rendering it ineffective.
likelihood of the drug’s degradation in the stomach by the acidic
environment or enzymes (e.g., peptide drugs like insulin and FACTORS INFLUENCING COLON-SPECIFIC DRUG
gonadorelin), or a high risk for first-pass metabolism (e.g., DELIVERY AND COLONIC BIOAVAILABILITY
corticosteroids).
Several factors may influence the formulation/
LIMITATIONS OF COLONIC DRUG DELIVERY development of a colon-specific drug delivery system
(CDDS) and the colonic bioavailability of the drugs (2,6).
The development of a colon-specific drug delivery system is Some of these factors are briefly discussed below.
associated with specific limitations and challenges. A predominant
and an obvious challenge is the fact that the colon is located in the Anatomical/Physiological Factors
distal part of the gastrointestinal tract (GIT). An orally adminis-
tered dosage form has to traverse the entire alimentary canal in The human large intestine is approximately 1.5-m long and
order to reach the target site. The GIT physiology is complex and forms the colon (ascending, transverse, and descending), with a
has a wide range of pH values, fluid volumes, and transit times. small distal part forming the rectum. The colon is 2–3 in. in
Moreover, the presence of food and metabolic enzymes also diameter, and its lumen is lined with mucus. The physiology of
increases the physiological complexity. These factors are an obsta- the colon differs significantly from other segments of the gastro-
cle to the reliable and efficient delivery of drugs to the colon. intestinal tract (GIT) (Table II). Moreover, the physiology and
Another factor is the drug solubility. Due to a low colonic luminal the physical properties of the colonic contents also differ be-
fluid volume, higher viscosity, and a neutral pH, the solubilization tween the ascending, transverse, descending, and sigmoidal co-
of the drug could be a rate-limiting factor for colonic absorption. lon. In addition, there exists variability in movement of food and
Finally, maintaining the stability of the drug in the colon can be a dosage forms across the colon, which may present a challenge in
matter of concern. The non-specific interactions of the drug with the development of colonic drug delivery systems (7). Another
Colon-Targeted Oral Drug Delivery Systems 733

Table II. Variations in the Physiology of Human Gastro-intestinal Tract (2,77,84)

Organ Contents pH

Stomach Thin soluble mucus, HCl, intrinsic factor, pepsin, lipases, gastrin, histamine, serotonin, somatostatin 1–1.5
Small intestine Chyme (from stomach), alkaline mucus, intestinal juice which is mostly water, motilin, 5–7.5
cholecystokinin, brush border enzymes (maltase, sucrose, lactase, enterokinase and
carboxypeptidase) Bile (which contains electrolytes, fatty substances, bile salts and pigments),
pancreatic juice (a bicarbonate-rich fluid containing enzymes)
Cecum Mucus, enteric bacteria, vitamins, food residue, gases such as carbon dioxide and methane 5.5–7
Ascending colon Mucus, enteric bacteria, vitamins, food residue, gases such as carbon dioxide and methane 5.7–6.9
Transverse colon Mucus, enteric bacteria, vitamins, food residue, gases such as carbon dioxide and methane 5.8–7.4
Descending colon Mucus, enteric bacteria, vitamins, food residue, gases such as carbon dioxide and methane 6.3–7.7
Rectum Undigested food residues, mucus, epithelial cells from the intestinal lining, numerous bacteria ~7
(millions), some remaining water

physiological factor that affects colonic drug delivery and bio- as it transits from the ascending colon towards the descending
availability is the variation in pH of the GIT. Significant intra- colon, resulting in a reduced drug dissolution and mucosal
and inter-subject variability in the pH of the GIT have been absorption (17). Viscosity also influences the penetration of
observed between disease states, fasted/fed states, sexes, and the drug into the disease-causing bacteria in the colon. The
ages in humans (8–10). Factors such as the viscosity and volume mobility of bacteria in the colon has been shown to be depen-
of colonic fluids, the presence of microbial enzymes, and the dent on the viscosity of colonic contents (18).
resulting colonic metabolism are other important factors influ-
encing CDDS performance which is discussed further. Colonic pH

Intestinal-Colonic Transit Time The pH varies significantly between different regions of

the GIT. For example, the pH of gastrointestinal contents can
The intestinal-colonic transit time plays an important role be as low as 1 to 2 in the stomach and rise to 7.5 in the distal
in the performance of CDDS and the colonic bioavailability of small intestine (19,20). The pH then declines from the end of
drugs. The transit times are also influenced by colonic disease the small intestine to the colon and gradually increases once
states such as UC and CD. Patients with UC are known to again in the colon (19,20). The pH of the colon may be
have shorter colonic times (~24 h) compared to healthy sub- influenced by a carbohydrate rich diet. This is due to the
jects (~52 h) (11). Similarly, Rana et al. showed that in patients fermentation of polysaccharides by colonic bacteria and sub-
with IBD, the orocecal transit time was delayed (12). The sequent formation of short chain fatty acids (21). Similarly,
transit of dosage forms generally depends on the time of polysaccharide-based drugs may also alter colonic pH.
administration, presence/absence of food, and the type of Laxative drugs like lactulose are known to be fermented by
dosage form. Stubbs et al. studied the effect of dawn and dusk colonic bacteria to produce lactic acid and reduce colonic pH
on the motility of dosage forms in the colon. The results (22). Gastrointestinal disease states such as UC have also been
showed that colonic transit was delayed during sleep, and found to influence the colonic pH (23). The pH of the colon
larger dosage forms, e.g., capsules transited faster compared affects the pharmacokinetic and pharmacodynamic behavior
to smaller dosage forms, e.g., dispersed particles (13). of a CDDS by influencing the solubility of drugs in the colonic
fluid. Moreover, if one or more components of the dosage
Colonic Fluid Volume form are pH-sensitive, for example, a pH-sensitive coating
membrane, the effect of colonic pH is even more pronounced
The average human food intake is approximately 1.5 kg/ on the drug release.
day and mainly consists of undigested proteins, carbohydrates,
and fats. These food components may serve as substrates for Colonic Enzymes and Metabolism
the microbial enzymes in the colon (14). The colon has a high
water-absorbing capacity and can absorb ~90% of the water The colon is known to consist of over 400 different spe-
entering the colon (15). The colonic fluid volume is calculated cies of aerobic and anaerobic microorganisms like Escherichia
to be in the range of 1–44 ml with an average volume of coli and Clostridium species, respectively (24). These bacteria
approximately 13 ml (16). Due to this low volume of colonic contain several hydrolytic and reductive metabolizing
fluids, the dissolution of drugs from the dosage forms becomes enzymes (25). The colonic enzymes catalyze a range of reac-
challenging and may affect the local drug bioavailability. tions, including the metabolism of xenobiotics (e.g., drugs) and
other biomolecules (e.g., bile acid), deactivation of harmful
Viscosity of Colonic Luminal Contents metabolites as well as carbohydrate and protein fermentation
(26). Polysaccharides such as chitosan, guar gum, pectin, etc.,
Due to a higher water-absorbing capacity, the viscosity of are commonly employed as release rate-controlling compo-
the colonic luminal contents is higher than upper GIT contents nents in colon-targeted dosage forms. These polysaccharides
and presents a challenge for the dissolution of CDDS. are known to be resistant to gastric and intestinal enzymes, but
Moreover, the viscosity of the contents progressively increases are metabolized by anaerobic bacteria in the colon (27–29).
734 Amidon et al.

Drugs are also known to be susceptible to biotransformation the prodrug approach by conjugating metronidazole with pec-
by colonic enzymes. The metabolism of drugs by the colonic tin and compared the drug release from this formulation to
enzymes may result in the formation of metabolites that are that from pectin microspheres which physically entrapped the
pharmacologically active, inactive, or sometimes even harmful drug (41). The pectin-metronidazole (PT-ME) prodrug
(30,31). Formation of a pharmacologically active metabolite showed significantly reduced drug release in the upper GIT
by the colonic metabolism of drugs is a commonly used “pro- compared to pectin microspheres containing metronidazole.
drug” approach for the colon-specific drug delivery systems In vitro and in vivo studies revealed that conjugating the drug
(32). to pectin can successfully target its delivery to the colon since
no drug release occurred at an acidic pH from the PT-ME
Formulation Factors prodrug while nearly 100% of the metronidazole physically
entrapped in pectin microspheres was released in this same
The formulation factors that influence colonic drug deliv- environment. A significantly higher fraction of the drug was
ery and bioavailability includes physicochemical properties of released from the PT-ME prodrug in the colon (41).
the drugs, the dose, and the dosage form factors. Due to the Another way to assist a drug formulation to remain intact
lower amount (1–44 ml) of colonic fluid available for dissolu- as it passes through the stomach and small intestine is for it to
tion, the solubility and the dose of a drug become important be covalently linked to a carrier. A drug can bind to carrier
factors for its colonic bioavailability. Although the highly molecules such as cyclodextrin, glucuronide, dextran, and
potent drug budesonide (dose, 9 mg) has a lower aqueous amino acids. It can also be linked to a carrier through an azo
solubility, it is absorbed well in the colon and is used bond. All of these bonds are broken down by colonic bacteria
successfully in the treatment of UC (33). Mesalamine has or enzymes (3). Modasiya et al. studied the use of sodium
a significantly higher solubility (3.64 mg/ml) compared to alginate (Na-Alg) and hydroxypropyl methylcellulose
budesonide (0.24 mg/ml); however, it also has a significantly (HPMC) as carriers for the successful delivery of matrix,
higher dose (4.8 g daily) which becomes a rate-limiting factor enteric-coated, and compression-coated tablets of curcumin
for its colonic absorption (34). Finally, the technology used in to the colon (42). The in vitro results showed that the drug
the dosage form development can also influence the colonic release was rapid from the matrix, and from the enteric-coated
bioavailability of drugs. Useris® and Entocort EC® are current- tablets in conditions representing the stomach and small in-
ly approved budesonide products for the treatment of UC and testine. It was also observed that increasing HPMC levels
CD, respectively (35). Useris® is a multi-matrix (MMX)-based significantly restricted the release of curcumin in the upper
delayed-release tablets, which ensures the drug release in the GIT and assisted in the delivery of curcumin specifically to the
colon, while Entocort EC® is a capsule which releases the drug colon.
in the ileum to treat CD.
Colon-Specific Biodegradable Delivery Systems
CONVENTIONAL APPROACHES FOR ACHIEVING
COLONIC DELIVERY The colon contains many species of anaerobic bacteria
which obtain their energy by fermenting substrates such as
Prodrugs polymers which have not yet been digested. Bacteroides,
eubacteria, clostridia, enterococci, and enterobacteria are
Prodrugs are inactive derivatives of a drug molecule some examples of these colon-specific species, and they pro-
which release the active ingredient once they are hydrolyzed duce numerous enzymes such as glucuronidase, xylosidase,
by enzymes such as those in the colon (2,36). In order to nitroreductase, and azoreductase to ferment these polymers
optimize drug delivery specific to the colon, the extent of this (10,43,44). Since these enzymes are localized to the colon, this
hydrolysis should be minimal in the upper portions of the appears to be a more promising approach for colon-specific
gastrointestinal tract and much more extensive in the colon. delivery (4,45). Polymers used in the development of CDDS
Azo conjugates are one of the most researched groups of can be chemically modified, and these modifications can in-
compounds that fall into this category (37,38). However, this fluence the extent of enzymatic degradation. For example,
is not a very flexible method because it relies on the functional Roos et al. synthesized the acetyl derivative of guar gum
groups of the drug molecule (4). Kim et al. synthesized a (AcGGM) and used this polymer to make a hydrogel of
prodrug of metronidazole, which was metabolized to the ac- bovine serum albumin (BSA) (46). They observed that the
tive drug, metronidazole when placed in rats’ cecal contents rate of hydrolysis for modified AcGGM by β-mannase was
(39). Unlike metronidazole, this prodrug did not metabolize in affected by its degree of substitution (DS). As DS increased,
the small intestine, and the systemic absorption of this prodrug the hydrolysis rate actually decreased, indicating that the side
was also found to be much lower compared to that of oral chain hindered the enzyme. On the other hand, the addition of
metronidazole (39). In another study, Kim et al. prepared a β-mannase significantly enhanced BSA release, with 95% of
prodrug of metronidazole, using a sulfate group, and showed the BSA released after 8 h in the presence of this enzyme, and
that that this formulation remained intact in the upper intes- only 60% was released in its absence. Azo-aromatic polymers,
tine, but was cleaved in the presence of rat cecal contents and which are among the most researched groups of compounds
active metronidazole was released. Similar to the first pro- used as prodrugs, are susceptible to degradation by azoreduc-
drug, much less of the conjugated prodrug was degraded and tases (18,19). Therefore, they can be used to coat the drug
absorbed in the small intestine compared to the active drug molecules such as peptides to protect them from degradation
after oral administration. Therefore, a minimal amount was by peptidases in the stomach and small intestine while still
absorbed into systemic circulation (40). Vaidya et al. utilized permitting drug release in the colon. Hita et al. carried out a
Colon-Targeted Oral Drug Delivery Systems 735

study in which metronidazole capsules were coated with a film released when the BAM reached the colon and was equally
of azo-aromatic polymers, and polymers sensitive to pH. The pharmacologically effective compared to marketed
in vitro and in vivo results revealed that the microbiota specific formulations.
to the colon degraded these polymers and released the met-
ronidazole locally in the colon (47).
Multiparticulate Systems
Matrix-Based Systems
Multiparticulate systems have a smaller particle size com-
pared to single-unit systems, and studies have shown that they
Another approach towards colon-targeted drug delivery
can reach the colon more quickly since they pass through the
includes embedding the drug in polymer matrices to trap it
GI tract more easily (1,53). Microspheres are one example of
and release it in the colon. These matrices can be pH-sensitive
a multiparticulate system that can be loaded with a drug for
or biodegradable. Ahmad et al. developed matrix tablets con-
colonic delivery. Microspheres that are prepared using biode-
taining metronidazole using a natural polymer called Assam
gradable components can be taken up by macrophages (1).
Bora rice starch (48). The prepared tablets were evaluated by
Chourasia et al. carried out in vitro drug-release studies on a
in vitro drug release studies using 0.1 N HCl, phosphate buffer
metronidazole multiparticulate system consisting of cross-
with a pH of 7.4, and goat cecal content. The results showed
linked chitosan microspheres coated with pH-sensitive
that the tablets exhibited a sustained release of the drug in the
Eudragit® polymers (52). Metronidazole was released only
alkaline environment, which was believed to be due to erosion
after Eudragit® polymers dissolved in the alkaline pH of the
and dissolution of the polymer during its prolonged exposure
small intestine. Since there was increased drug release in the
to this environment (48). The release of the drug, however,
presence of rat cecal contents, chitosan was thought to be
was observed throughout the GIT. This indicated that these
susceptible to degradation by colonic enzymes. Vaidya et al.
matrix tablets were not colon-specific delivery systems, but
developed a multiparticulate system in which microspheres of
rather controlled-release systems.
the polysaccharide pectin were coated with a pH-sensitive
polymer, Eudragit® S 100 (41,54). The in vitro drug release
Timed-Release Systems studies showed that no metronidazole was released at the
acidic pH of the stomach. However, once the system was in
Timed-released formulations are based on the drug being a more alkaline environment of the colon, metronidazole was
released in the colon after a specified amount of time (3). This released continuously. Metronidazole release was found to be
approach is dependent on the transit time through the small even more significant in the presence of rat cecal contents
intestine, which is and known to vary between 3 and 4 h (2,49). indicating that this system was biodegradable, in addition to
Gastric emptying time is inconsistent between individuals and being pH-sensitive. Furthermore, the metronidazole concen-
also fluctuates depending on food intake (50). Additionally, tration in various parts of the GIT as shown through in vivo
diseases associated with the colon, such as irritable bowel studies also demonstrated the ability of this system to target
syndrome and ulcerative colitis can influence transit time this drug specifically to the colon. Perera et al. synthesized and
through the colon (4). Gazzaniga et al. used a combination evaluated microparticles based on a pectin-4-aminothiophenol
of pH-sensitive polymers and a timed-release approach to (Pec-ATP) conjugate and observed that these particles were
achieve colon-specific delivery (51). A formulation consisting much more stable in vivo, than unmodified pectin micropar-
of a drug-containing core enclosed within three polymeric ticles (55). These particles thus appeared to be a better option
layers (a hydrophilic layer sandwiched between two pH- for colon-targeted delivery based on this study. In a recent
sensitive layers) was developed. The in vitro evaluation results study, Liu et al. developed guar gum base microspheres for the
revealed a sustained drug release due to pH protection and colonic delivery of budesonide (56). The in vitro release stud-
hydrogel formation. ies showed that these microspheres extended the release of
budesonide over 24 h. The in vivo evaluation of the colon
Bioadhesive Systems targeting and pharmacokinetic studies showed that the pre-
pared budesonide microspheres effectively delivered budeso-
Bioadhesive systems allow a formulation to remain in nide to the colon in high concentrations.
contact within an organ, in this case the colon, for a long Beckert et al. synthesized and evaluated a multiparticu-
period of time to assist poorly absorbable drugs to be late system in which the drug in the core of the formulation
absorbed (48,52). Some of the polymers which have been consisted of two forms of pellets (57). The first type of pellet,
explored as bioadhesive components for these systems include pellet A, contained an inner polymer coating which allowed
polycarbophils, polyurethanes, and polyethylene oxide (3). the drug to be released continuously and an outer polymer
Ahmad et al. used Assam Bora rice starch to develop a bio- which broke down only at a pH greater than 5.5. The polymer
adhesive microsphere (BAM) for targeting the delivery of coating on pellet B limited the drug release to less than 20%
metronidazole to the colon (48). These BAMs were found to after 6 h at pH 6.8. However, more than 50% of the drug was
have higher retention time in the colon, and helped increase released within the same time period at pH 7.2. Therefore, the
absorption of the drug in the colon. The in vitro drug release combination of these two forms of pellets with their polymer
studies showed that only 10–12.5% of the metronidazole was coatings was found to be promising for a targeted drug deliv-
released on conditions representing the stomach and less than ery to the colon. Agarwal et al. in a recent study prepared and
25% was released in a simulated small intestine. However, characterized calcium alginate-carboxymethyl cellulose (CA-
over 90% of the drug was rapidly released in cecal content. CMC) beads for colon-specific oral drug delivery (58). The
Additional in vivo studies showed that the drug was only researchers explored the combined properties of CA-CMC,
736 Amidon et al.

i.e., pH sensitivity, degradation by colonic microflora, and phthalate (HPMCP) have solubilities which are pH-depen-
preferential colonic mucoadhesivity in designing colon- dent. They are insoluble in highly acidic conditions, but when
specific delivery of 5-flurouracil, an anticancer drug. The the pH reaches a certain range they dissolve. The pH at which
in vitro drug release results showed that the CA-CMC beads the polymer dissolves varies depending on the extent of ester-
were able to significantly extend the release of the drug be- ification. Some examples of carbohydrate mixtures which
yond 24 h. Additionally, the CA-CMC beads were demon- have been studied include pectin-HPMC, chitosan-HPMC,
strated to have a significantly high mucoadhesiveness at chitosan-pectin, guar gum-chitosan, and dextran-chitosan
colonic pHand degrade in the presence of colonic microflora. (64–66).
The use of nanoparticles as carriers for orally adminis- As mentioned in the previous sections, polysaccharides
tered drugs targeted to the colon has also been reported such as pectin, chitosan, chondroitin sulfate, galactomannan,
previously (59–61). Studies have shown that these nanoparti- and amylose are ideal materials for achieving colon-specific
culate systems improve the bioavailability of these drugs due delivery because they can be degraded by the colonic enzymes
to their increased surface area and thus increased contact with and are harmless to the organisms. The use of these polysac-
biological surfaces. Nanoparticles are also taken up by macro- charides in thin film coatings is believed to have the potential
phages at inflamed regions of the colon, which allows the to allow for increased drug delivery to the target regions at a
system to remain at the target site for a prolonged period of faster rate, compared to other formulations which utilize these
time. However, the nanoparticulate systems must be protected materials within matrix systems or as compression coatings.
from being taken up by Payer’s patches or degraded by Pectin is a hydrophilic polysaccharide which can modify
enzymes before reaching the colon in order for this approach drug release due to its gelling ability. An insoluble poly-
to be successful. Calabrese et al. prepared nanotechnology- mer such as ethyl cellulose (EC) is often mixed with the
based hybrid formulations of metronidazole and K10- pectin in the coating layer to help reduce water perme-
montmorillonite (MMT-K10) clay, and carried out kinetic ability and protect the drug core (67). Wakerly et al.
and equilibrium studies to determine the release of MNE from mixed an aqueous dispersion of EC (Surelease®) with
this clay (60). The results showed that these newer nanopar- pectin to coat tablets of paracetamol (68). These film
ticle formulations allowed for longer action in the colon. It was coatings had various pectin/EC ratios, and after evaluating
also found that an enteric coating is unnecessary due to low the coated tablets in vitro, the results showed that the rate of
drug release in the simulated gastric fluid. drug release increased as the amount of pectin in the film
increased. The drug diffused through the EC as well as through
pores which formed in the film coating after pectinolytic
Polysaccharide-Based Delivery Systems enzymes degraded the pectin (68).
Polysaccharide-based delivery systems have several
advantages and are therefore becoming a popular option for Colon Targeting by Coatings
colon-specific delivery of drugs. Some of the advantages with
polysaccharide use include availability, easy modifications, Incorporating the drug in the pH-sensitive polymers al-
stability, safety, and biodegradability (4). Mundargi et al. com- low for delayed release by protecting the active ingredient
pared several polysaccharides for their usefulness in colon- from the acidic pH of the stomach and proximal small intes-
targeted metronidazole delivery (62). The results showed that tine. These polymers then break down in the more basic pH of
the release rate of metronidazole does depend on the nature the terminal ileum, thus providing a targeted drug delivery to
and the concentration of the polysaccharide used in the for- the colon (1,3). Although the solubility of these polymers
mulation. Gauri et al. used various amounts of xanthan gum increases as pH rises, there are some disadvantages to this
and guar gum to prepare matrix tablets of metronidazole (63). approach. The pH fluctuations along the GIT can cause the
The in vitro evaluation of tablets in 0.1 N HCl, pH 7.4 phos- formulation to dissolve early in the small intestine and the lag
phate buffer, and pH 6.8 phosphate buffer with 4% w/v rat time can be too long at the ileo-cecal junction and ascending
cecal content showed that the amount of drug released from colon (4). Some examples of commonly used pH-sensitive
the matrix tablets during the first 5 h, which represented time polymers in the design of colon-targeted drug delivery systems
spent in the stomach and small intestine, ranged from 12 to include methacrylic-acid based polymers, also known as
33%. It was also observed that the increasing xanthan gum Eudragit® (2,36).
content in the matrix tablets delayed the drug release and Enteric-soluble polymers are resistant to dissolution in
caused them to be more susceptible to colonic enzymes. the acidic environment of the stomach, but can dissolve at
The use of a combination of polysaccharides in CDDS the higher pH values of the intestine. These polymers have
has been found to be more effective for achieving colon- been studied extensively for their use as coatings in formula-
specific delivery compared to the use of a single polysaccha- tions intended to deliver active pharmaceutical ingredients
ride. Cellulose derivatives are frequently used in combination specifically to the colon (Fig. 1). Polymers based on poly-
to develop these delivery systems because cellulose is not methacrylate such as Eudragit® L and Eudragit® S have
absorbed systemically when administered orally. There are frequently been used for this purpose, and each one has its
two groups of cellulose esters which can be used in drug own unique pH value at which it dissolves. These two poly-
formulations. Non-enteric cellulose esters such as cellulose mers have been mixed in different ratios to form a coating
acetate are insoluble in water and their solubility is indepen- with an optimized dissolution rate. Additionally, coatings with
dent of pH. These can be used in insoluble, permeable coat- these polymers are designed to be relatively thick to prolong
ings. The enteric cellulose esters such as cellulose acetate their dissolution, and provide a controlled or an extended
phthalate (CAP) and hydroxypropyl methylcellulose drug release (69). Obitte et al. investigated the capability of
Colon-Targeted Oral Drug Delivery Systems 737

Fig. 1. Schematic representation of the cross-section of the enteric-coated colon-targeted drug

delivery system

the hydrophobic polymers Landolphia owariensis latex (LOL) release. Most of these orally administered systems consist of a
and Eudragit® L-100 to control the release of metronidazole drug-containing core, coated with a polymer (74). Film coat-
aimed at colon targeting (70). The in vitro dissolution studies ings used for pulsatile delivery include rupturable, permeable,
showed that drug release increased with increasing pH. The and semipermeable coatings.
Eudragit® L 100 and LOL also demonstrated an additive Rupturable film coatings allow a drug to be released after
effect on delaying and then increasing drug release at pH 7.4 undergoing a timed disruption caused by hydrostatic pressure
over an extended period of time. within the core (69). Since these polymeric films are perme-
In addition to enteric-soluble polymers, acid-soluble pol- able, an influx of water and subsequent swelling of the hydro-
ymers have also been investigated as potential agents to be philic polymers can initiate the disruption. Permeable film
used in colon-targeted formulations. The pH of the proximal coatings allow water to pass through and dissolve the drug-
large intestine decreases in those with IBS. For example, the containing core, but the polymeric coating itself is insoluble.
colonic pH is typically 6.4–7.0 for a healthy person, but can These coatings do not rupture after exposure to an aqueous
drop to 2.3–4.7 with someone who has UC (71). Leopold et al. medium because they are permeable and resistant to dissolu-
developed dexamethasone minitablets coated with the acid- tion. Additionally, the materials within these coatings do not
soluble polymer Eudragit® E and found that the Eudragit® E expand after an influx of water. Since it takes time for the drug
coating rapidly dissolved in the buffers at pH 2.0–5.0 allowing to diffuse out from the core after dissolving, this results in a lag
the drug to be released within 10–50 min. However, the extent phase before drug release occurs (69).
to which the drug released was delayed in the pH 6.8 buffer Another type of time-dependent coating is a semiperme-
depended on the composition of the drug core as well as the able film coating which is similar to permeable coatings in that
coating thickness. (69,71). they are permeable to water (75). However, these coatings are
Compression-coating (tablet-in-a-tablet), also known as impermeable to solutes. Water moves into the tablet core of
Bdry coating^ is a tablet coating technique where the core the formulation due to osmotic pressure, and when the hydro-
tablet (containing the drug) is coated with a coating- static pressure within the system exceeds the osmotic pressure
excipient (powder) on a tablet press. This technique has after a programmed lag phase, small orifices in the outer
gained interest in the formulation development in recent years membrane allow the drug which has dissolved in the aqueous
due to the dry nature of dosage form development, i.e., avoid- medium to be pumped out (76).
ing the process complexities and stability challenges associat-
ed with spray coatings (wet, hot). Several researchers have
explored this technique for the development of colon-specific INTEGRATED APPROACHES FOR ACHIEVING
oral solid dosage formulations. COLONIC DELIVERY
Yassin et al. applied a granulated chitosan coating to a
colon-targeted tablet formulation of 5-fluorouracil using In recent years, several integrated approaches have been
compression-coating with a goal of targeting this drug specif- explored to achieve colon-specific drug delivery. These
ically to the colon for a more effective treatment of colon approaches utilize physiological factors such as luminal pres-
cancer with less toxic side effects (72). The in vitro evaluation sure, or physical phenomena such as osmotic pressure in the
of the formulation showed that increasing the thickness of the design of the delivery systems.
coating resulted in a progressive decrease in the drug release
at acidic pH. Additionally, the in vivo studies showed that this
formulation did not break down until it reached the large Pressure Controlled Delivery
bowel. Recently, Kadiyam et al. developed an almond-gum,
matrix-based colonic drug delivery system of tramadol HCl, Peristaltic motion causes the luminal pressure of the large
compression-coated with Eudragit® S100 (73). The study intestine to increase more than that of the small intestine
results showed that compression-coated tablets successfully because its contents are more viscous due to the reabsorption
delayed the release of tramadol HCl over 24 h. The in vivo of water (77). Several studies have been carried out to utilize
X-ray imaging studies in rats revealed that the compression- the colonic luminal pressure to develop colon-specific drug
coated tablets efficiently delivered the drug to the colon with- delivery systems. Takaya et al. developed capsules that deliver
out being disintegrated in the upper GIT. a drug to the colon based on luminal pressure (78). Although
Pulsatile drug delivery systems are time-dependent for- these systems allow for drugs to be delivered to the colon
mulations that are designed to release the drug after a pre- rather than the small intestine due to higher colonic pressure,
dictable period known as the Blag phase^ (74). The pulsatile reabsorption of water from the colon causes its content to be
systems which are currently being studied do not depend on highly viscous which may become an obstacle for site-specific
the different environmental conditions of the GIT for the drug delivery (4,79).
738 Amidon et al.

Fig. 2. Schematic representation of the cross-section of the OROS-CT colon-targeted drug delivery system

Osmotic Controlled Delivery encompasses an osmotic push compartment as well as a drug

compartment. The water causes the push compartment to swell
Although the concept of osmotic controlled drug delivery and forms a gel in the drug compartment that is forced out of an
has been around for several years, the applications of this tech- orifice through the membrane next to the drug compartment.
nology in the design of colon-specific oral dosage forms have The rate at which the drug flows out depends on the rate at
gained popularity only in the 10–15 years. The OROS-CT is an which water enters. To prevent drug release in the small intes-
example of a system regulated by osmotic pressure. It consists of tine, these systems can also be designed such that there is a lag
a hard gelatin capsule which dissolves in the pH of the small time between when the enteric coating dissolves and the drug is
intestine and allows water to enter the unit. This then causes it to released (80).
swell and the drug is forced out (3). Within each capsule there
can be as many as 5–6 units, and each unit is surrounded by a Pulsincap Systems
drug impermeable enteric coating which prevents water from
entering in the acidic environment of the stomach (Fig. 2). Time-dependent systems are not always ideal for delivering
However, this coating dissolves and the water enters once the drugs to the colon due to variability in the gastric emptying time
capsule enters the higher pH of the small intestine. Within the and the changes in gastrointestinal transit due to peristalsis or
enteric coating there is a semipermeable membrane which disorders such as IBS. Therefore, the integration of a timed-

Fig. 3. Schematic representation of the mechanism of the pulsincap colon-targeted drug delivery system
Colon-Targeted Oral Drug Delivery Systems 739

release system with pH-sensitive properties can be beneficial in 5. Kumar P, Mishra B. Colon targeted drug delivery systems—an
achieving colon-targeted delivery. A pulsincap system is one overview. Curr Drug Deliv. 2008;5(3):186–98.
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example of a formulation that utilizes both these techniques Biopharmaceutical considerations and characterizations in devel-
(81,82). The system consists of a water insoluble capsule body opment of colon targeted dosage forms for inflammatory bowel
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