Natural and Synthetic
Polymers for Colon Targeted Drug Delivery
Babli Thakur, Vinay Pandit,
Mahendra Singh Ashawat, Pravin Kumar*
Department
of Pharmaceutics, Laureate Institute of Pharmacy, Kathog,
Kangra (H.P)-177101
*Corresponding Author E-mail: kumar3785@gmail.com
ABSTRACT:
Colon targeted drug delivery system have recently gained importance in
delivery of number of therapeutic agents for both local and systemic action.
Colon targeted drug delivery system is useful for delivery of proteins and
peptides, drugs undergoing degradation in stomach and small intestine.
Targeting of drugs to colon is also favorable for the chronotherapy of
diseases. To achieve successful, colonic delivery, a drug is needed to be
protected from absorption in upper gastrointestinal tract (GIT). Out of the
several approaches for colon targeting, coating the drug core with a polymer or
polymer combinations is an important strategy. Coating of drug core with a pH
dependent polymer or a polymer biodegraded in colon by colonic flora has been
widely investigated approach for colonic delivery. Polysaccharides are
important polymers from either natural or synthetic origin which have been
exhaustively studied for successful colon targeting. This review describes some
important natural and synthetic polysaccharides and polymers investigated for
colonic drug delivery by coating the drug core.
KEY WORDS: Colon, polymer, coating, biodegradation, polysaccharide.
INTRODUCTION:
Oral
route is most widely used for controlled delivery of drugs. It offers several
advantages such as prevention of peak and valley fluctuation, reduced dosing
frequency, reduced dose, improved patient compliances and nearly constant level
at the site of action.1, 2In past decades, via oral route colon has
been exhaustively investigated as a specific site for delivery and absorption
of drugs.
Colonic
drug delivery has gained increased importance not just for the delivery of the
drugs for the treatment of local diseases associated with the colon like Crohn’s disease, ulcerative colitis, irritable bowel
syndrome and constipation but also for the systemic delivery of proteins,
therapeutic peptides, anti-asthmatic drugs, antihypertensive drugs and
anti-diabetic agents.3, 4 Because of near neutral pH and longer
transit time colon offer several therapeutic advantages as a site of drug
delivery.5
Colon
specific release of drug either immediate release or controlled release for
local treatment, will help in reduction of drug dose and doing frequency.6It
will further reduce the cost of therapy, lower incidence of adverse effects and
thus, improved patient compliance. Moreover, the timed release of drug to colon
can be used for the chronotherapy of diseases such as
nocturnal asthma, depression, diabetes mellitus etc.7
Bioavailability of certain drugs viz. NSAIDs (irritant to gastrointestinal
tract) and drugs having high first pass metabolism can be improved by
delivering directly to colon. The prolong retention time (6-12hours) and more
hostile environment of colon (less enzymatic activity) compared to stomach and
small intestine, also helps in the absorption of poorly water soluble drugs.
Further, colon can also be used as site for delivery and absorption of proteins
and peptides due to absence of peptidase.8,9 There are certain
limitations associated with the development of colonic drug delivery system
such as multiple manufacturing steps and incomplete drug absorption due to
interference from dietary residues, intestinal secretions, mucus and fecal
matter.10 Certain approaches (e.g. pH sensitive coating) used to develop colon targeted drug delivery system showed
uncertainty of location and environment in which formulation may start to
dissolve.11
There
are several approaches which had been widely investigated for the design of
colon targeted drug delivery systems (Table 1). The desired properties of a
colon targeted drug delivery system can be achieving by using some polymer
either alone or in combination because it is now recognized that polymer can
potentially influence the rate and absorption of drug release and play an
important role in the formulation of colon targeted drug delivery system.12,
13Coating of delivery systems with a polymer either sensitive to colonic
pH or biodegraded by bacteria in colon is an important approach for the
formulation of colon targeted drug delivery system.14 In the present
paper, the authors have tried to explain the basic mechanism of colon targeting
by polymer coating, important polymers of natural or synthetic or semisynthetic origin and patents granted for drug delivery
to colon by coating approach.
Mechanism
of colon targeting using polymer coating
In
this approach, the drug is present in the core of the formulation which is
coated with layers of polymer. The change of pH along the gastrointestinal
tract has been used as a mean for the solubilization of polymer coating and
drug release in colon (Fig 1). This can be achieved by means of coating that
remain intact at lower pH of the stomach but should dissolve at neutral pH of
the colon. The pH in the gastrointestinal tract varies from 1.2 in the stomach,
6.6 in the proximal small intestine, about 7.5 in the distal part of small
intestine and 6.7 in colon.16-18
The
pH variation in the stomach and small intestine has previously been used to
deliver drugs to small intestine by way of pH sensitive enteric coating. These
polymer coats are recalcitrant to the acidic condition of the stomach but
ionized and get dissolved above a certain threshold alkaline pH found in small
intestine. Thus, it was possible to apply same concept to deliver drugs to the
terminal of ileum or colon by use of enteric polymers with a relatively high
threshold pH for dissolution and subsequent drug release.19
Table 1. Different approaches used for colon targeted drug
delivery system15
Approaches |
Basic features |
1.Prodrug (covalent linkage with carrier) |
|
1.1 Azo conjugated e.g. sulphasalazine
with 5-ASA |
Drug is conjugated with an azo bond |
1.2 Glycoside conjugate e.g. dexamethasone |
Drug is conjugated with glycoside |
1.3 Glucuronide conjugated |
Drug is conjugated with glucuronide |
1.4 Polypeptide conjugated |
Drug is conjugated with polypeptide |
1.5 polymeric conjugation |
Drug is conjugated with polymer |
2. Approaches to deliver the intact drug to the colon |
|
2.1 Coating with polymer |
|
2.1 (a) Coating with pH sensitive polymer |
Formulation coating with enteric coated polymers release polymer when
pH moves toward alkaline pH |
2.1 (b) Coating with biodegradable polymer |
Drug released with degradation of polymer due to the action of colonic bacteria |
2.2 Embedding in
matrices |
|
2.2 (a) Embedding in biodegradable polymer and hydrogel |
Drug release depend upon the swelling and biodegradation action of the
polymer |
2.2 (b) embedding with pH sensitive polymer |
Release depend upon the degradation of pH sensitive polymer |
2.3 Time released
system |
Once multicoated formulation passes the stomach, drug is released after
lag time 3- 5 h i.e. equivalent to transit time of small intestine |
2.4 Redox
sensitive polymer |
Drug formulated with azo and disulfide
polymer that selectively response to the redox
potential of colon |
2.5 Bioadhesive
system |
Bioadhesive
polymer selectively target and release the drug in colon |
2.6 Osmotic controlled
drug delivery |
Drug is released through semipermeable
membrane due to osmotic pressure |
Fig
1.Mechanism of drug release from pH sensitive polymer coating
Fig
2.
Mechanism of drug release from biodegradable polymer coating
Drug
can be also administered locally and selectively to the colon if they are
enclosed in an azo-aromatic cross-linked polymer
subject to cleavage by azo-reductase of the colonic
micro flora. This approach of coating a drug with biodegradable material for
the colon targeting was reported to deliver large amount of the drug.
Biodegradable polymers degrade in vivo,
either in presence of enzyme or non-enzymatically, to
produce products which are non-toxic and biocompatible (Fig 2).20 The colonic bacterias will enzymatically degrade the polymers (mainly polysaccharides)
into organic acid. Various bacteria present in the colon secrete many enzymes
which can cause hydrolysis of glycosidic bonds e.g.C-D glactosidase, amylase, pectinase, C-D glucodase, dextranase and D-D xylosidase.21The micro flora
composition remains relatively constant across a diverse human population.
Natural
polymers:
Natural
polymers mainly polysaccharide has gain importance for the formulation of solid
oral dosage forms for colonic delivery of drugs because these are non-toxic,
safe and economical. Polysaccharides are biodegradable polymers having limited
swelling characteristic in acidic pH due to their hydrophilic nature.22These
polymer are economical and are available in a variety of structures. Linear
polysaccharides remains intact in stomach and small intestine, but the bacteria
of human colon degrades them and thus make them potentially useful in colon
targeted drug delivery systems.23Pectin, inulin,
xanthan gum, starch, guar gum, amylose
and khaya gum etc. are few polysaccharides investigated
for colon targeting of drugs.
PECTIN:
Pectin
(Fig. 3a) are non-starch linear heterogeneous polysaccharide that consist of
D-1, 4 D-glacturonic acid and 1, 2 D-rhamnose with glactose and darabinose side chains. It is refractory to gastric and small
intestine enzymes but is almost completely degraded by the colonic bacterial
enzyme to produce a series of soluble oligalactorunate.24, 25 Pectin
is soluble in water, monovalent cations
(alkali) metal salt of pactinic and pactinic acid are soluble in water, di
and tri-valiant cations are weakly soluble or
insoluble. If used alone it swells, when it comes in contact with gastric
fluids and intestinal fluid.26
Dupuis et al. had investigated zinc pectinate beads for colonic delivery of ketoprofen.
This study revealed that zinc pectinate beads
protected the entrapped drug sufficiently from the upper gastro-intestinal
conditions and release was controlled by pectin degradation with colonic
microflora.27
Lee
CM et al. had used spray drying method to prepare pectin microspheres for oral
colon delivery of indomethacin. The prepared
microspheres were cross-linked with calcium chloride. The release of indomethacin from the cross linked pectin microspheres was
more suppressed than its release from non-cross linked microspheres. Drug
release from pectin microspheres was increased by the addition of pectinase. Release of indomethacin
from pectin microsphere was less in acidic pH while it was stimulated at
neutral pH (pH 7.4). The results of the study clearly demonstrated that pectin
microspheres prepared by spray drying and crosslinking
methods are potential carriers for colon-specific drug delivery.28
Momin M et al. mixed
film of pectin: ethyl cellulose for colon targeted drug delivery of sennosides and triphala was
prepared using non aqueous solvent like acetone and isopropyl alcohol. The
results of the study indicated that under simulated colonic conditions, drug
release was more pronounced from coated formulations containing higher
proportion of pectin.29
Wei
H et al. performed in vitro and in vivo study of
pectin/ethyl cellulose film-coated pellets of 5-fluorouracil for colon
targeting. The pellet cores were coated to different film thicknesses with three different pectin: ethylcellulose
formulations. The pectin: ethylcellulose (1:2) coated
pellets with 30% total weight gain produced more satisfactory drug-release
profiles in simulated gastric, intestinal and colonic fluids.30
Ravi V et al. formulated and
evaluated a novel colon targeted tablet using pectin as a carrier. The
release of drug was limited in stomach and small intestine; and was maximum in the colon. The study revealed that pectin can be
used effectively for colon targeting of both water soluble and insoluble drugs.31
CHITOSAN:
Chitosan (Fig 3b) is a
high molecular weight polycationic polysaccharide
derived from chitin by alkaline deacetylation. Chitosan is consisting of a repeated unit of
(2-amino-2-deoxy-D-gluco-pyranose) which is linked by (1-4) C-bond. Chitosan is a nontoxic, biodegradable, biocompatible, and
bioactive polymer. It is used as colon targeted drug delivery because it has
tendency to dissolve in acidic pH of stomach but get swollen in the intestinal
pH.32
Orienti I et al.
developed a colon specific drug delivery system composed of drug reservoir and
the outer drug release regulating layer by dispersing chitosan
powder in a hydrophobic polymer. It was observed that the thickness of the
outer layer control the drug release rate since the dispersed chitosan dissolves easily under acidic conditions. An
additional outer enteric coating was also provided to prevent the release of
drug from chitosan dispersed system in the stomach.33
Shimono N et al.
investigated chitosan to control the release of many
drugs and to improve the bioavailability of degradable substances such as
protein, as well as to improve the uptake of hydrophilic substances across the
epithelial layer in colon.34
Zhang
H et al. formulated and investigated hydrogel beads
of chitosan with tripolyphosphate
and protein release was investigated in vitro under different conditions. It was observed that
under colonic environment, protein release was high due to the degradation of
the beads.35
Shu X et al. used chitosan capsules for colonic delivery of an antiulcerative colitis drug. 5-Aminosalicylic acid (5-ASA)
was used as model drug. A marked increase in the release of drug from chitosan capsule was observed in the presence of the rat cecal content. It was concluded, that chitosan
capsules could be an effective carrier for the colon targeted delivery of
anti-inflammatory drugs.36
GUAR GUM:
Guar
gum (Fig 3c) is a polysaccharide composed of the sugars galactose
and mannose. The backbone is a linear chain of C 1, 4-linked mannose residues
to which galactose residues are 1, 6-linked at every
second mannose, forming short side-branch.37
Al-
Saidan SM et al. investiated
guar gum in colon targeted drug delivery systems due to its drug release
retarding property and susceptibility to microbial degradation in large
intestine. Guar gum has a gelling property which retards the release of drug
from the dosage form, making it more likely that degradation will occur in the
colon. Guar gum was found to be a colon-specific drug carrier in the form of
matrix and compression coated tablets as well as microspheres.38
Krishnaiah YS et al.
prepared core tablets containing 5-aminosalicylic acid (5-ASA) by wet
granulation with starch paste. The tablets were compression coated with
different quantities of guar gum. The study confirmed that selective delivery
of 5-ASA to the colon can be achieved using guar gum as a carrier in the form
of compression coating over the drug core.39
Ji CM et al.
evaluated the potential of guar gum as a film coating material for colonic
delivery of 5-flourouracil. Guar gum based pellet systems were prepared by
coating guar gum and pH-sensitive polymer Eudragit FS
30 D sequentially around drug-loaded cores. The study revealed that guar gum
coating worked as a time-controlled retardant and offered additional protection
to the pellets until it is degraded by microbial enzymes at the proximal
colon. In vitro results
indicated that guar gum is a feasible coating material to achieve timed and
enzyme-triggered fluorouracil release.40
Krishnaiah et al. has
performed the pharmacokinetic evaluation of guar gum-based colon-targeted
tablets of mebendazole against an immediate release
tablet in six healthy human volunteers. Colon-targeted tablets showed delayed tmax (9.4±1.7 h) and absorption time, and
decreased Cmax (25.7±2.6 μg/ml) and absorption rate constant when compared to
the immediate release tablets. The results indicated that the guar gum-based
colon-targeted tablets of mebendazole did not release
the drug in stomach and small intestine, but delivered the drug to the colon
resulting in a slow absorption of the drug and making the drug available for
local action in the colon.41
AMYLOSE:
Amylose (Fig 3d) is the
polysaccharide which is obtained from the plant extracts and a component of
starch. Amylose is unbranched
linear polymer of glucopyranose units (α-1,
4-D-glucose) linked through α–D-(1-4) linkage. Amylose
is resistant to pancreatic amylases in its glassy amorphous form but it gets
degraded by the bacteroids, bifidobacterium.42
Milojevis S et al. formed an amylose film
by gelation, which can be used for tablet coating
purpose. But, coating made up of amylose solely
becomes porous and release the drug under simulated gastrointestinal
conditions. To avoid this problem, water insoluble polymers are added to the amylose film as these water insoluble polymers control the amylose swelling. Addition of ethyl cellulose to amylose gives a suitable polymer mixture for colon
targeting. In vitro dissolution of various coated pellets was
performed under simulated gastric and intestinal conditions and it was
concluded that amylose: ethyl cellulose coat (1:4)
resist these conditions over a period of 12 h.43
Cumming et al. used a mixture of amylose and ethocel (1:4) to
prepare microspheres of [13C] glucose which was used as a surrogate
for drug delivery. The results of the study revealed that combination of amylose and ethylcellulose can be
used for coating of pellets which results in controlled release of contents for
targeted delivery of drug to the large bowel during a period of 12–24 h.44
LOCUST
BEAN GUM:
Locust bean gum (Fig 3e) contains
natural polysaccharides which have a molecular weight of 310000. Locust bean
gum is also known as ‘Carob gum’ as it is derived from the endosperm of the
seed of the ‘Carob’ (Ceratonia Siliqua Linn,
Fam: Leguminosae).
It is irregular shaped molecule with branched β-1, 4-D-galactomannan
units. Locust bean contains about 88% D-galacto-D mannoglycan, 4% of pentane, 6% of protein, 1% of cellulose
and 1% of ash.45
Raghavan et al. investigated a combination of locust bean gum and chitosan, as a coating material for protecting the core
tablet containing mesalazine during the condition
mimicking mouth to colon transit. The coating was susceptible to the colonic
bacterial enzymes which causes the release of drug.45
Bashardoust et al. formulated
compression-coated tablets of ibuprofen by a direct compression method using
locust bean gum (LBG) at 300, 250, 200 and 175 mg. Tablets were evaluated for
their physicochemical properties and in
vitro drug release. In vitro drug
release studies were performed with and without rat caecal
contents. In rat caecal contents, tablets showed
enhanced drug release due to degradation of the LBG coating by colonic enzymes.
The in vitro release studies in pH
6.8 phosphate buffer containing 2% w/v rat caecal
contents showed the cumulative percentage release of ibuprofen after 26 h as
39.91 ± 0.05%, 53.21 ± 0.37%, 69.17 ± 0.19% and 94.46 % ± 0.92%. Coating
thickness and the amount of locust bean gum control the release rate.46
INULIN:
Inulin (Fig 3f) is a naturally occurring glucofructan
and consists of C 2-1linked D-fructose molecule having a glycosul
unit at the reducing end. It can resist the hydrolysis and digestion in the
upper gastrointestinal tract.47 Inulin is
not hydrolysed by the endogenous secretion of human digestive
tract. However, bacteria harbouring in the colon and
more specially bifidobacteria are able to ferment
inulin.48
Maris B et al. synthesized and
characterized new hydrogel systems composed of methacrylated inulin,
copolymerized with the aromatic azo agent BMAAB and
HEMA or MA. Inulin hydrogels
have been developed and characterized for dynamic and equilibrium swelling
properties and in vitro degradation study. The rate of water
transport into the inulin hydrogels
was quite high (mean swelling time <1.2 h) and the hydrogels
exhibited anomalous dynamic swelling behavior. The enzymatic digestibility of
the prepared inulin hydrogels
was assessed by performing an in vitro study using an inulinase preparation derived from Aspergillus Niger. The amount of fructose liberated from the inulin hydrogels by the action of
inulinase was quantified using the anthrone method. The equilibrium swelling ratio as well as
the mechanical strength of the hydrogels was studied
before and after incubation in inulinase solutions.
The data obtained by these different methods indicate that enzymatic digestion
of the inulin hydrogels
appeared to be enhanced by a prolonged degradation time, a higher inulinase concentration, and a lower degree of substitution
and feed concentration of the hydrogel polymer. The inulin hydrogels exhibited an
increase in equilibrium swelling after degradation compared with the swelling
before degradation, suggesting that inulinase enzymes
diffuse into the inulin hydrogel
networks causing bulk degradation.49
Fig 3.
Chemical structure (a) Pectin (b) Chitosan (c) Guar
gum (d) Amylose (e) Locust bean gum (f) Inulin
XANTHAN
GUM:
Xanthan gum (Fig 4a) is a high molecular weight extra cellular
polysaccharide produced by the fermentation of the gram negative bacterium Xanthomonas campestral. It is a free flowing powder
soluble in both hot and cold water and gives viscous solution at low
concentration. It is a very effective thickener and stabilizer because it gives
highly viscous solutions even at low concentration in comparison to the other
polysaccharide solution. Its solution offer very good stability. They are least
affected by change in pH and are stable in both alkaline and acidic conditions.50
Shun YL et al. used xanthan gum and hydroxypropyl
methyl cellulose as hydrophilic matrixing agent for
preparing modified release tablets of diazepam HCl.
The amount of hydroxy propyl
methyl cellulose and xanthane gum exihibited
significant effect on drug release from the tablets prepared by direct
compression technique. It was concluded that by using a stable blend of hydroxy propyl methyl cellulose
and xanthane gum desired modified drug release could
be achieved.51
Musukula YR et al.
developed compression coated tablets of Ketorolac tromethamine (KTM) for colon targeting. Thenatural
polymers like Xanthan Gum, Guar Gum, Khaya Gum and Combination of Xanthan
Gum/ Guar Gum with HPMC K100M were investigated as a compression coat over the
KTM core tablets. The tablets were evaluated for their pre and post compression
parameters. In vitro drug release
studies were conducted in pH1.2 buffer, pH7.4 phosphate buffer and in enzyme
free simulated intestinal fluid (pH6.8) and also in pH 6.8 phosphate buffer
containing 2% and 4% w/v of rat caecal contents,
respectively. A significant difference was observed in the amount of KTM
released at the end of 24hin medium with rat caecal
content when compared to the without rat caecal
content.52
KHAYA
GUM:
Khaya gum (Fig 4b) is a polysaccharide obtained from the incised
trunk of tree Khayagrandulifolia,
family Maliaceae.
Odeku O.A. et al., evaluated
the effect of khaya gum on the mechanical release
properties of paracetamol tablets in comparision with
two standard binding agents, poly vinyl pyrrolidone
and gelatin. It has been found that the crushing strength, friability ratio,
disintegration time, dissolution time t50, t90 and t1hr
all increase in binder concentration.
It was also found that khaya gum is capable of protecting the drug from being
released in the acidic environment prevailing in the stomach and small
intestine. They are degraded by the colonic bacterial enzyme, there by
releasing the drug in colon where there is local action and improved
absorption.53
Prabhakara P et al.
prepared fast disintegrating core tablets of budesonide
by direct compression technique. These tablets were coated with khaya gum. These tablets were further coated using eudragit S-100 by dip coating technique. In vitro drug release studies were
carried out in presence and absence of rat caecal
contents and revealed that khayagum, protected the drug from being released in the upper parts
of the GIT to little extent. But, the enteric coated formulations completely
protected the drug from being released in the upper parts of the GIT, and
released the drug only in the colon by bacterial degradation of gum. Khaya gum alone cannot be used either for targeting the
drug to the colon or for sustaining or controlling the release of drugs.54
SYNTHETIC
POLYMERS:
The polymer used for colon
targeting, however, should protect the drug from the environment and absorption
in upper gastrointestinal tract. It should not be affected by the lower pH of
stomach and the proximal part of the small intestine and also able to
disintegrate at the neutral slightly alkaline pH of terminal ileum and
preferably at the ileocecal junction. These can be
called as pH dependent polymer. The most commonly used pH dependent polymers
are derivatives of acrylic acid and cellulose. Thus, drug is targeted with pH
sensitive polymer to the colon.55
EUDRAGIT:
Eudragit products are pH-dependent methacrylic
acid polymers containing carboxyl groups. The number of esterified
carboxyl groups affects the pH level at which dissolution takes place. Eudragit are of three types: Eudragit
L, Eudragit S and Eudragit
RS.56
Euragit L
Eudragit L (Fig 4c) is an anionic polymer synthesized from methacrylic acid and methyl methacrylate
having a pH dependent solubility. Eudragit®
L 100 would release the drug at pH rang 6-6.5 i.e. ileum and large intestine.
It is a white powder having faint characteristic odor.57
It provides an effective and stable
enteric coating with a fast dissolution in the upper bowel. It is also used to
form a site specific drug delivery system to the intestine by combination with Eudragit® S100. Eudragit
L coating have been investigated in the development colon targeted single unit
tablets of 5-ASA in patients with ulcerative colitis.58
Eudragit S
Eudragit S (Fig 4d) is an anionic copolymer synthesized from methacrylic acid and methyl methacrylate.
It is available only in the form of organic solution i.e. isopropanol
and solid. Eudragit® S 100 releases the
drug at pH rang above 7.0.57
It is used in powder form for
granulation of drug substance in order to form a controlled release drug
delivery system. It is used for the delivery of drug in the intestine by
combination of drug with other grades of Eudragit S
such as Eudragit® S12.5 Eudragit® FS 30 D. When sites of disintegration
of Eudragit S coating single-unit tablets were
investigated using a gamma camera they were found to lie between ileum and splenic flexure. Eudragit S has
been used in combination with Eudragit L 100-55, in
colon specific drug delivery.58
Pruthviraj S et al. prepared colon targeted tablets of budesonide using pectin, guar gum as enzyme dependent
polymers along with HPMC, HEC as time dependent polymers followed by pH
dependent polymers like Eudragit S100 and Cellulose
acetate phthalate. The compression coating was done over the core tablets by
using pectin, guar gum, HPMC and HEC in different ratios by direct compression
method. The enteric coating was done on the compression coated tablets by using
ES100 and CAP in different ratios by dip coating method. In vitro swelling and in
vitro drug release studies were carried out at different pH (1.2, 6.8 and
7.4). The compression coated formulation C1 (pectin: guar gum =1:2), C2 (HPMC:
HEC =1:2) and C3 (HPMC and HEC: pectin and guar gum =2:1) showed good swelling
(493.42%, 411.08% and 393.61%) up to 18, 20 and 21 h, respectively. pH dependent
polymers ES100: CAP in the ratio 2:1 as an enteric coating material applied
over compression-coated tablets was capable of protecting the drug from being
released in the stomach and small intestine. This study proved that Budesonide compression-coated tablet, enteric coated with
ES100: CAP in the ratio 2:1 may be beneficial in the treatment of irritable
bowel syndrome and nocturnal asthma.59
SELLAC
Shellac (Fig 4e) is the purified
product of natural resin lac which the hard secretion
of small, parasitic insects Kerrialaca. It is the
only kwon commercial resin of animal origin. It is a hard, brittle and resinous
solid which is insoluble in water. It is practically odorless, but evolve
characteristic odor on heating. The shellac coating remains intact during
passage through stomach and intestine until it reaches in the colon. This
allows the transfer of drug into the colon. Moreover, activity of peptidase in
the colon is lower in the upper GI tract allowing for oral administration of
peptide and proteins.60
Shellac films prepared from
alcoholic solution shows pronounced hardening including by continuing
polymerization process. This results in a loss of gastric resistance time and a
decrease in intestinal fluid solubility. These are disadvantages when compared
with synthetic or partially synthetic polymer such as polymethacrylate
and cellulose derivatives.61
Das
M et al. prepared matrix tablets with Pectin and Hydroxy
propyl methylcellulose (HPMC) K4M and compression
coated with Eudragit S100, Shellac and HPMC K100M.
The prepared tablets were evaluated by compatibility studies. The tablets
passed the physical parameter tests. The in-vitro release studies revealed that
the release pattern of the tablets was mainly influenced by the type of
coating, the release being minimum for HPMC K100M
coated tablets and maximum for Eudragit S100 coated
tablets. Shellac coated tablets gave an average rate of release throughout the
8 hour study. It was concluded that among the various batches prepared, FBC1
(HPMC K4M tablets coated with HPMC K100M), FAC1(Pectin tablets coated with HPMC
K100M) and FAC2 (Pectin tablets coated with Shellac) were found to avoid
significant drug release in the first 5 hours of dissolution and released 35%,
10% and 54% drug throughout the 8 hour dissolution study.62
Fig
4.
Chemical structure (a) Xanthane gum (b) khaya gum (c) Eudragit® L
100 (d) Eudragit ® S 100 (e) Shellac
Table 2. Patents granted in relation to
polymer coating for colon targeted drug delivery systems
Patents |
Details of patents |
US70488945 |
It explained
a time controlled drug delivery system. The inventor coated the drug particle
with a plasticized enteric coating cellulose acetate phthalate, HPMC
phthalate etc. The inventors also
added an option of applying an organic acid (such as fumaric
or succinic acid) for further modulation of lag
time and release profile of the drug. |
CA2215378 |
It is
assigned to Andrx Pharmaceuticals Inc., US
describes unit dosage forms of diltiazem
hydrochloride which comprise a two fraction system of enteric polymeric
membrane coated pellets and delayed pulse polymeric membrane coated pellets.
This invention relies on the biological system for subject-to-subject and
dissolution of the complete enteric coat for bio-response in the initial phase. |
US6217904 |
It described
a pharmaceutical dosage form for pulsatile delivery
of a CNS stimulant. The formulation included three fractions of beads; first
fraction of beads being prepared by coating an inert support material such as
lactose with the drug which provides immediate release. A second fraction of
beads was prepared by coating immediate release beads with an amount of
enteric coating material. A third fraction was prepared by coating immediate
release beads having half dose of the first fraction of beads with a greater
amount of enteric coating material, sufficient to provide lag phase of 7-9 h and thereafter releasing
the drug in the colon. |
US5439689 |
It disclose
once-a-day oral formulation of diltiazem
hydrochloride having a stair stepped release profile generated by two
populations of diltiazem beads which released the
drug at two different intervals of time i.e. 3-9 h following lag times of 3 h
and 15-21 h following a lag time of 15 h. Although such a formulation
releases diltiazem hydrochloride over 24 h. |
US655136 |
It explains
the use of hydrocolloid gums which are effective to provide for colonic
delivery e.g. guar gum, locust bean gum, tragacanth
etc. Other material suitable for colonic delivery includes polysaccharide and
related compounds e.g. pectin, chitosan, chondroitin sulfate etc. The invention is based on
pharmaceutical dosage form for pulsatile delivery
of methylphenidate by using three kinds of mini-tablets or bead or particle
fractions in a capsule which have different drug and polymer coating levels.
Out of which the third tablet or bead or particle fraction provides for
release of the active agent in the colon. |
Important patents granted for polymer
coating
There
have been several patents granted for polymer coating approach for colon
targeted drug delivery systems (Table 2).63
CONCLUSION:
Colon targeted drug delivery system
is a novel approach to improve the patient compliance and therapeutic effect. During
the last decade several natural and synthetic polymers have been investigated
for delivery of drugs to the colon. Formulations coated with natural or
synthetic biodegradable and pH sensitive polymer passes intact from upper GIT
(stomach and small intestine) and release the drug in colon. One of important
class of natural polymers is the polysaccharides having a wide application for
the development of colon targeted drug delivery systems by coating. Eudragit and shellac have also shown some promising results
for delivering the drug to the colon.
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Received on 30.12.2015 Accepted
on 21.01.2016
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Right Reserved
Asian J. Pharm. Tech. 2016; Vol. 6: Issue 1, Jan. - Mar., Pg 35-44
DOI: 10.5958/2231-5713.2016.00006.4