REVIEW OF LITERATURE… 5 2.1. ANATOMY OF COLON The digestive tract is the system of organs within multicellular animals that takes in food, digests it to extract energy and nutrients, and expels the remaining waste. The major functions of the GI tract are ingestion, absorption and defecation. In a normal human adult male, GIT is approximately 6.5 metres (20 feet long) and consists of upper and lower GI tracts. The upper GI tract consists of the mouth, pharynx, oesophagus and stomach. The lower GI tract comprises the small intestine, large intestine and anus.A Large intestine is wider and shorter than the small intestine (approximately 1.5 metres in length as compared to 6.7 to 7.6 metres in length for the small intestine). The colon is 1.5 cm long and it itself is made up of caecum, the ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon and the sigmoid colon. The structural features are depicted in Figure 2.1 and anatomical features of small intestine & large intestine are summarised in Table 2.1. Figure 2.1 Structural features of large intestine
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REVIEW OF LITERATURE…
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2.1. ANATOMY OF COLON
The digestive tract is the system of organs within multicellular animals
that takes in food, digests it to extract energy and nutrients, and expels the
remaining waste. The major functions of the GI tract are ingestion, absorption and
defecation.
In a normal human adult male, GIT is approximately 6.5 metres (20 feet
long) and consists of upper and lower GI tracts. The upper GI tract consists of the
mouth, pharynx, oesophagus and stomach. The lower GI tract comprises the small
intestine, large intestine and anus.A Large intestine is wider and shorter than the
small intestine (approximately 1.5 metres in length as compared to 6.7 to 7.6
metres in length for the small intestine). The colon is 1.5 cm long and it itself is
made up of caecum, the ascending colon, hepatic flexure, transverse colon,
splenic flexure, descending colon and the sigmoid colon. The structural features
are depicted in Figure 2.1 and anatomical features of small intestine & large
intestine are summarised in Table 2.1.
Figure 2.1 Structural features of large intestine
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Table 2.1 Anatomical features of small intestine and large intestine
Organ Characteristics
Small Intestine
Duodenum It is 25-30 cm long section. It serves as a receiving area for chemicals and partially digested food from stomach.
Jejunum
It is about 40% of the small gut in man. It comes in contact with large number of intestinal cells containing thousands of tiny finger like projections called villi which increases surface area to absorb most of the nutrients into blood
Ileum It is about 60% of the intestine in man. It contains goblet cells and peyer’s patches. Here remaining nutrients are absorbed before moving into the large intestine.
Large Intestine
Caecum It is about 6-7 cm in length. It is the pouch where the large intestine begins. It is where ileum opens from one side and continues with the colon.
Ascending colon.
It is about 20 cm long. It is the part of the large intestine that goes from the bend on the right side below the liver and the caecum.
Hepatic flexure
It is on the right side of the body near the liver. It is the right angle bend in the colon that marks the connection of the ascending colon and transverse colon.
Transverse colon
It is about 45 cm long. It is the largest and most mobile part of the colon (Meschan, 1975). It attaches the ascending colon to the descending colon by crossing the abdominal cavity. Its diameter varies from 9 cm in caecum to 2 cm in sigmoid colon; its average diameter is about 6.5 cm (Mrsny, 1992).
Descending colon
It is about 30 cm long. It traverses inferiorly along the left abdominal wall to the pelvic region.
Sigmoid colon
It is about 40 cm long. It is the part of the colon that forms an angle medially from the pelvis to form an S-shaped curve.
Rectum
It is about 12 cm in length. It is a short, muscular tube that forms the lowest portion of the large intestine and connects it to the anus. Faeces collects here until pressure on the rectal walls cause nerve impulses to pass to the brain, which then sends messages to the voluntary muscles in the anus to relax, permitting expulsion.
Source:-David, 1992
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The colon serves following important functions:
1. Creation of suitable environment for the growth of colonic
microorganisms.
2. Absorption of potassium and water from the lumen concentrating the
faecal contents, secretion and excretion of potassium and
bicarbonate ions (Watts and Illum, 1997).
3. Through the muscular movements of colon faecal matter is pushed along
until finally, the walls of the sigmoid colon contracts, causing the faeces to
move into the rectum.
4. Synthesis of vitamin K by colonic bacteria promotes a valuable
supplement to dietary sources and makes clinical vitamin K deficiency
rare.
The colon is mainly situated in the abdomen; the rectum is primarily a
pelvic organ. Further, the histological and microscopic structural evaluation of
colon shows four layers: serosa, the mascularis externa, the submucosa and the
mucosa (Figure 2.2 - 2.3).The serosa is the external coat of the large intestine and
consists of aerolar tissue that is covered by single layer of squamous mesothelial
cells. The major muscularis coat of the large intestine is the muscularis externa.
This is composed of an inner circular layer of fibers that surrounds the bowel. The
submucosa is the layer of connective tissue that lies immediately beneath the
mucosa. The colonic mucosa is further divided into three layers: the muscularis
mucosae, the lamina propria and the epithelium.
Figure 2.2 Histological features of Colon (Source:- Harshmohan, 2003)
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Figure 2.3 Microscopic structure of colon (Source:- Kaye et al.,
1973)
2.2 CHALLENGES IN THE DESIGN OF COLONIC DELIVERY
DOSAGE FORMS
Formulations for colonic delivery are, in general, delayed-release dosage
forms which may be designed either to provide a ‘burst release’ (Pinhasi et. al.,
2004) or a sustained/prolonged release once they reach the colon. The proper
selection of a formulation approach is dependent upon several important factors,
which are listed below:
a) Pathology and pattern of the disease, especially the affected parts of the
lower GI tract or physiology and physiological composition of the healthy
colon if the formulation is not intended for localized treatment.
b) Physicochemical and biopharmaceutical properties of the drug such as
solubility, stability and permeability at the intended site of delivery, and
c) The desired release profile of the active ingredient.
Formulation of drugs for colonic delivery also requires carefull
consideration of drug dissolution and/or release rate in the colonic fluids.
Generally, the dissolution and release rate from colonic formulations is thought to
be decreased in the colon, which is attributed to the fact that less fluid is present in
the colon than in the small intestine (Takaya et. al., 1998). The poor dissolution
and release rate may in turn lead to lower systemic availability of drugs. These
issues could be more problematic when the drug candidate is poorly water-soluble
and/or requires higher dose for therapy. Consequently, such drugs need to be
delivered in a presolubilized form, or formulation should be targeted for proximal
colon, which has more fluid than in the distal colon (Basit and Bloor, 2003).
Mesalamine, Sulfasalazine, Balsalazide, Infliximab, Azathioprine and Mercaptopurine
Irritable bowel syndrome
Abdominal pain or cramping, a bloated feeling, flatulence, diarrhea or constipation —people with IBS may also experience alternating bouts of constipation and diarrhea, mucus in the stool
A change in bowel habits, narrow stools, rectal bleeding or blood in stool, persistent abdominal discomfort, such as cramps, abdominal pain with bowel movement, unexplained weight loss
5-Flourouracil, Leucovorin, Oxaliplatin, Irinotecan, Bevacizumab and Cetuxim B
Diverticulitis
Formation of pouches (diverticula) on the outside of the colon due to bacterial infection
Bactrim, Flagyl, Sulfatrim Metronidazole
Antibiotic associated
colitis
Overgrowth of Clostridium difficile and its subsequent toxin production
Clindamycin, Broad-Spectrum Penicillins (Eg, Ampicillin, Amoxicillin) and Cephalosporins
Hirschsprung's disease
Severe form of constipation in which bowel movement occurs only once or twice a week
polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP) and
shellac. Eudragits are preferred coating materials for this purpose since they
dissolve at pH ≥ to 5. A list of few commonly used enteric polymers is given in
the Table 2.9
pH-sensitive calcium alginate-coated gelatin microspheres have been
developed by Rao and Ritschel (1992). The calcium alginate coat is obtained by
crosslinking sodium alginate with calcium chloride. The formulation is a pH-
controlled system because the alginate coat is protonated at gastric pH and ionized
at intestinal pH. Drug release from the drug-loaded microspheres occurs
predominantly in the ileocecal region.
Kelm and Manring et al. (1996) developed a dosage form for colonic
delivery wherein enteric polymer coating material dissolved in an aqueous media
ranging in pH from 5 to 6.3. The enteric polymer coating had a coating thickness
of 250 µm. Dextramethasone was sprayed on sugar spheres. These spheres were
then coated with HPMC as barrier coat and subsequently with CAP. Sugar
spheres sprayed with mesalamine were coated with Eudragit L. Similarly,
propranolol base and salmon calcitonin were separately formulated in self-
emulsifying vehicles, filled in soft elastin capsules and coated with CAP.
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Table 2.8 Approaches and challenges for formulation of colon -specific drug delivery system
Approaches
Challenges Principle of delivery
pH dependent
systems
Stomach pH (1-3) Proximal small intestine pH(7.5) Distal small intestine pH (7.5) Caecum (6.4) Transverse colon (6.8) Descending colon (7.0)
Enteric polymers do not dissolve in stomach and at pH ≥ 5 they begin to dissolve
Time dependent
Systems
Wide variation in gastric retention time Increased transit time in diseases such as inflammatory bowel syndrome, ulcerative colitis, diarrhoea
Swelling type polymers that allow drug release 4-6 h after leaving stomach
Microbially triggerd systems
Polysaccharide based delivery systems
Prodrugs
Gums are hydrophilic and gel forming Colonic microflora varies with diet, age and disease Microbial degradation of azo polymers is slow, drug delivery is thus incomplete and irregular
Polysaccharides not digested by stomach and intestinal enzymes. Polysaccharides secreted by colonic bacteria degrade polysaccharides. Prodrugs cleaved to active moiety by the bacterial enzymes present in colon.
Kelm et al. (1997) prepared bisacodyl formulations where bisacodyl
sprayed sugar spheres coated with barrier coat were further coated with CAP or
Eudragit L. Similarly, bisacodyl soft gelatin capsules coated with CAP were
observed to provide an enteric coating.
Torres et al. (1998) formulated multiparticulate microspheres consisting of
hydrophobic core coated with a pH-dependent polymer for colonic specific drug
delivery. Microspheres were loaded with budesonide and coated with enteric coat
of Eudragit S, by emulsion-solvent evaporation technique for the local treatment
of intestinal disorders.
Raheja et al. (2004) formulated mesalamine tablets by coating with
Eudragit S100 to a weight build up of about 3% w/w (about 35 µ coat thickness).
The in vitro dissolution of mesalamine from these tablets was compared with
Asacol DR tablets. It was observed that even under stressed conditions
encountered during variable gastric residence times in stomach and intestine, the
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formulated tablets provided a more consistent and predictable release profile,
releasing mesalamine only at pH 7.2.
Table 2.9 Enteric polymers utilized in development of modified-release formulations for colonic delivery
Polymer Threshold pH
Eudragit® L 100 6.0
Eudragit® S 100 7.0
Eudragit® L –30D 5.6
Eudragit® FS 30D 6.8
Eudragit® L 100-55 5.5
Polyvinyl acetate phthalate 5.0
Hydroxy propyl methyl cellulose phthalate 4.5-4.8
Hydroxy propyl methyl cellulose phthalate 50 5.2
HPMC 55 5.4
Cellulose acetate trimelliate 4.8
Cellulose acetate phthalate 5.0
The plasma concentration of mesalamine was significantly higher after oral
administration of formulated tablets as compared to that after commercially
available formulation. The extent of Asacol DR tablets was found to be 575.87
nghr/ml, which increased to1980.26 nghr/ml for Eudragit S100 coated tablets.
Many commercial drug formulations for the oral treatment of inflammatory bowel
disease (such as Asacolitin®, Claversal®, Salofalk® or Budenofalk®) are coated
with pH-sensitive enteric coating polymers such as Eudragit® L or S. These
polymers have a dissolution pH of between 6 and 7, and are intended to release
the drug as soon as the intestinal pH exceeds 6 or 7, respectively.
Biswajit et al. (2004) developed a suitable matrix type transdermal drug
delivery system (TDDS) of dexamethasone using povidone, ethylcellulose and
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Eudragit. Invitro results showed that PVP–EC polymers were better suited than
PVP–Eudragit polymers for the development of TDDS of dexamethasone.
Kawashima et al (2005) prepared the nanoparticles for the treatment of
inflammatory bowel disease using tacrolimus entrapped in to pH-sensitive
microspheres.
2.3.2 Time – Dependent systems
Time-controlled systems are useful for synchronous delivery of a drug
either at pre-determined lag time such that patient receives the drug when needed
or at a pre-selected site of the GI tract (Savastano et. al., 1997). The lag time
usually starts after gastric emptying because most of the time-controlled
formulations are enteric coated.
Drug release from these systems is not pH dependent. These systems take
advantage of the relatively constant transit time through the small intestine and are
particularly useful in the therapy of diseases, which depend on circadian rhythms.
The lag time observed with the TIME-CLOCK™ system (Pozzi, et. al.,
1994; Wilding et. al., 1994) is caused by slow hydration of the hydrophobic
coating layer, which consists of wax, Tween-80 and HPMC. Drug release from
the coated tablets is pH-independent and there is little influence of agitation on the
lag time of drug release. Disaggregation of the tablets occurs in the proximal
colon after 5.5 hours.
Savastano et al. (1997) developed an osmotic delivery device for release
of the active ingredient to preselected region of gastrointestinal tract. The delivery
system consisted of solid core containing Metoprolol fumarate, delay jacket
coated over the core (e.g. dextrates, sodium alginate), followed by a
semipermeable membrane (cellulose acetate, CAP) and finally, an enteric coat.
Metoprolol fumarate core tablets were compression coated with dextrate followed
by film coating with cellulose acetate and finally with Eudragit (enteric polymer).
The amount of metoprolol released was negligible till 5 hr and 82.7% till 24 hr
when dissolution studies were carried out in 0.1N HCl for 0-2 hr followed by
phosphate buffer (pH7.5) for 2-24 hr. A unique composition wherein dissolution
of outer layer activated the process of swelling/ dissolution/ erosion of the
intermediate coating layer was described by Poli et al. (2001). Posatirelin tablets
coated with HPMC E50 LV were finally coated with CAP. These tablets did not
release posatirelin at pH lower than 5 for at least 2 hr. An increase in the pH of
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dissolution media to pH 7.5 also could not release the drug for subsequent 4 hr.
An additional exposure for 45min to pH 7.5 released the drug.
Takada (1997) described a similar time-controlled formulation in the form of
capsules and bilayered tablets. The release time of the drug from formulations is
controlled by disintegration lag-time which depends on the balance between the
tolerability and thickness of a water-insoluble membrane and the amount of a
swellable excipient such as low substituted hydroxypropyl cellulose (L-HPC) and
sodium starch glycolate. The shell of the capsule formulation is made up of ethyl
cellulose (EC), approximately 120 µm in thickness, which contains micropores at
the bottom of body. The fill material is composed of a solid dispersion
formulation of the drug filled into a capsule body also made of EC, and a tablet
containing L-HPC made by direct compression. Finally, a cap made up of EC is
attached to the body of outer EC capsule (Figure 2.8). After oral administration,
GI fluid permeates through the micropores and causes swelling of swellable
excipients. This causes an inner pressure, which pushes the drug container. Then
the disintegration of the capsules occurs with the breakdown of the capsule cap. In
this way, the disintegration of time-controlled capsule is dependent on the balance
between the swelling pressure of formulated L-HPC and the strength or
tolerability of the EC capsule.
Gazzaniga et al, (2001) formulated delayed release tablets of Antipyrine
using hydrophilic swellable polymer to achieve time or site specific release of drug.
Mastiholimath et al, (2006) developed pulsatile device to achieve time
and site specific release of theophylline. The device consists of insoluble hard
gelatine capsule body, filled with eudragit microcapsules of theophylline and sealed
with hydrogel plug.Invitro release studies of pulsatile device revealed that
increasing the hydrophilic polymer content resulted in delayed release of
theopyhlline from microcapsules.
A pressure-controlled drug delivery system that relies on the high pressure
in the distal colon produced by peristalsis has been introduced by Niwa et al. (1995)
and Takaya et al. (1997).
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Figure 2.8 Time-controlled capsule for colonic delivery
2.3.3 Pressure-Controlled Drug Delivery Systems
ethylcellulose coating, is induced by the pressure and thus the destructive force
produced by peristaltic waves, and depends on the thickness of the ethylcellulose
film. The capsule is filled with a solution of the drug and this should be
advantageous in view of the small amount of fluid in the distal colon, which could
compromise drug dissolution and absorption (Takaya et. al., 1998; Takada and
Murakami 2005).
The ability of Pressure controlled colon-delivery capsules (PCDCs) to
deliver a drug locally into the distal bowel was investigated in humans using
caffeine as a model drug. From this study it was indicated that the thickness of
ethyl cellulose film was an important factor in controlling the disintegration of the
Figure 2.21 Schematic representation of different type of cross-linking in chitosan molecules. (a) chitosan cross-linked with itself (b) hybrid polymer network (c) semi-interpenetrating network (d) ionic cross-linking (Source:-
Gurny et al.,2004)
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Table 2.17 Cross linking behaviour of chitosan
S.No. Type of cross linking
Type of network Cross linker References
1
Chitosan
cross-linked
with itself
Two structural units involved may or may not belong to same chitosan
Dialdehydes via Schiff
base.Glyoxal,Glutaraldeh
yde,Diethyl squarate,
oxalic acid and genipin
Angeli’s et. al., 1998;
Hirano et. al., 1990,
Monteiro and Airoldi,
1999 , Patel and Amiji,
1996), Aly, 1998).
Ballantyne and Jordan,
2001, Murata-Kamiya et.
al., 1997, Monteiro and
Airoldi, 1999
2 Hybrid
polymer
networks
(HPN)
One structural units belong to chitosan and other belongs to other polymeric chain
Poly ethylene glycol diacrylate, scleroglucan, gelatin, collagen or a silylating agent via glutaraldehyde
Airoldi and Monteiro,
2000, Kim et. al., 1995,
Crescenzi et. al., 1997,
Crescenzi et. al., 1995
3 Semi or full
inter
penetrating
polymer
network
(IPN)
In this network, one structural unit entrapped in to another polymer
Cold set gels (form gels on cooling the solution ) Heat set gels (form gels on heating the solution) Reentrant gels (from which galactose residues are removed)
(CTKP) using acrylonitrile in the presence of sodium hydroxide under different
reaction conditions. The results suggested that optimum CTKP (DS = 0.49) was
obtained when 0.008 mol (1.3 equivalent/OH group) of acrylonitrile was reacted at 30
ºC for 45 min using 0.026 mole TKP (0.07 mole of OH group) in 100 ml of water.
Further, the CTKP was observed to exhibit non- Newtonian pseudoplastic behaviour,
relatively high viscosity, cold water solubility, and good solution stability and clarity,
as compared to unmodified TKP. In another investigation, cyanoethyl cassia tora gum
(DS = 0.44) was produced by mixing 0.608 mol acrylonitrile and 0.625 mol sodium
hydroxide at 30ºC for 4 h (Sharma, Kumar, & Soni, 2003b).
2.7.2. Cross-linking of gums
1. Cross-linking with glutaraldehyde
Natural gums being hydrophilic swell in the presence of dissolution media. Hence,
there is a possibility of the entrapped drug leaking out prior to arrival of the drug at
its site of absorption. Thus, there is a need to reduce the enormous swelling of the
gums by cross-linking.
(i) Cross-linking of alginate-guar gum with glutaraldehyde:-
Alginate guar gum hydrogels were prepared with distinct alginate to guar gum
percent weight ratios. Guar gum solution was prepared, the required amount of
alginate was added and stirred well to form a uniform mixture. To this mixture
glutaraldehyde was added to a final concentration of 0.2% (v/v), blended, and
precipitated (in 0.5% w/v CaCl2) to form beads. The beads were washed with distilled
water to remove any residual glutaraldehyde and calcium chloride, and lyophillised
(George, & Abraham, 2007). This is depicted in Fig. 2.27A.
Glutaraldehyde has been used extensively for cross-linking polymers containing
hydroxyl groups. It was observed that with an increase in the concentration of
glutaraldehyde there was an increase in the cross-link density and as a result there
was a decrease in buffer uptake. Drying of the hydrogel to form discs introduced
irreversible changes in the hydrogel. Thus, it was observed that when discs were
formed by physical entanglements in the polymer network, it resulted in a change in
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A
B
4)--D-Manp-(1 4)--D-Glcp-(1O
O
O
CH2OH
O
OH
HOO
CH2OH
OCH2OH
O
O
OO
CH2OH
OHHO
OOH
HO
HOH2C
O
OH
HOO
CH2OH B(OH)4-
B
Figure 2.26 A) Grafting of konjac glucomannan (KG) with poly acrylic acid and B) complexation with Borax ions (B(OH)4
-).
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Figure 2.27 Cross linking of gums with A) glutaraldehyde; B) Tri sodium trimetaphosphate and C) grafting of guar gum with polyacrylamide (pAAm-g-GG) followed by crosslinking with glutaraldehyde.
A
B
C
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the degree of swelling. However, it was observed that high amounts of glutaraldehyde
were required for the cross-linking reaction suggesting that the cross-linking
efficiency was low. This could be attributed to a) low reactivity of guar gum hydroxyl
groups as a result of limited water solubility b) glutaraldehyde polymerisation during
the cross-linking process and c) possible masking effect of the hexose units of the
branched polymer. However, the cross-linked products retained the ability of guar
gum to be degraded in vitro by a mixture of galactomannase and α-galactosidase
(Kabir, Yagen, Penhasi, & Rubinstein, 1998).
In another investigation carried out by Soppirnath, Kulkarni, & Aminabhavi (2000)
interpenetrating network microspheres of polyvinyl alcohol and guar gum were
prepared. These microspheres were cross-linked with glutaraldehyde. The aldehyde
groups of glutaraldehyde reacted with the hydroxyl groups of the polymers to form
acetal cross-links. The IR spectra
exhibited a corresponding peak at 1251 cm-1. Similarly, DSC studies showed an
increase in ∆H value. This increase in the ∆H value may be attributed to the high
amount of energy required to break the highly cross-linked polymeric network
structure. This also suggested the formation of a highly crystalline polymeric matrix
due to increase in cross-linking agent density. The crystalline nature of the polymeric
matrix dictates its water uptake. An increase in cross-linking leads to formation of a
dense macromolecular network. Therefore, a decrease in molecular transport of liquid
within such polymeric matrices was observed, resulting in reduced swelling. The in
vitro release of nifedipine from these microspheres was observed to depend on the
extent of cross-linking. This was due to the fact that the solvent uptake by the
microspheres decreased with increased cross-linking. Thus, the drug release
continued for several hours. The release of the drug from these microspheres
increased initially due to the polymer relaxation process as water penetrated and
converted the glassy polymer into a rubbery one. However, the latter part of the
release profile from the fully swollen polymer was due to a diffusion process.
(ii) Cross-linked microspheres of polyacrylamide grafted guar gum (pAAm-g-GG) by
water-in-oil (w/o) emulsification method:-
5.0% (w/v) polymer solution (20 ml) was prepared and acidified with 5 ml dilute
sulfuric acid. In order to cross-link the polymer, 2.5, 5 or 7.5 ml of 25% (w/v)
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glutaraldehyde solution was added to the polymer solution separately. These
solutions were then emulsified into 100 ml of light liquid paraffin with 2% (w/v)
Tween 80. The hardened microspheres were filtered and washed repeatedly with
hexane and water to remove liquid paraffin, unreacted glutaraldehyde and any
adhered Tween 80. The hydrogel microspheres were then dried under vacuum at 40ºC
overnight and kept in a desiccator until further use (Soppirnath, & Aminabhavi,
2002). The scheme is depicted in Fig. 2.27C
2. Phosphate cross-linking of natural gums.
The high swelling characteristics of natural gums in matrices which leads to burst
release does not make them suitable for delivering drugs to distal parts of the gut.
Such high swelling can be prevented by phosphate cross-linking (Kabir, Yagen,
et al., 2004). Generally, phosphate cross-linked gums are prepared by dissolving
trisodium trimetaphosphate (STMP) in sodium hydroxide solution (1 M, pH = 11) at
room temperature for 30 min, followed by addition of gum under continuous stirring
(Fig. 6B). The dispersion is then stirred slowly to allow maximum swelling of the
gum. The mixture is finally poured into a Petri dish and dried. The dried hydrogel
obtained is rinsed several times with distilled water to remove unreacted STMP, gum,
and other soluble agents and dried to constant weight and stored until further use
(Fig. 2.27B).
3. Cross-linking with ions
Preparation of barium ion-cross-linked sodium alginate–CMGG beads:-
Sodium alginate and carboxymethyl guar gum (CMGG) were dissolved in distilled
water at a concentration of 4% (w/v). The polymer solution was then added drop-wise
into the gelation medium (BaCl2 solution of definite composition (w/v), 250 mL) at
room temperature. The beads, thus formed, were cured in the gelation medium for 20
min and then taken out, washed with distilled water and then allowed to dry to
constant weight at 30 ºC (Bajpai, Saxena, & Sharma, 2006).
4. Miscellaneous methods
Cross-linking of cashew gum with epichlorohydrin
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Cashew gum was mixed with sodium hydroxide solution (5 M, 2 ml) and distilled
water until a homogeneous paste was formed. Epichlorohydrin (volume in the range
of 0.4–0.86 ml) was then added to the mixture and kneaded to afford proper
homogenisation. The mixture was heated at 40ºC for 24 h, followed by a second
heating time of 15 h at 70ºC (Figs. 2.28). The cross-linked gel was washed with
distilled water, dialysed for 72 h against distilled water and finally, freeze-dried
(Silva, Feitosa, Maciel, Paula, & Paula, 2006).
Radiation-induced polymerisation of sterculia gum:-
Sterculia gum and definite concentration of monomers were dissolved in distilled
water (10 ml). The reaction mixture was irradiated with c-rays in a 60Co γ-chamber
for 24 h with a total dose of 53.14 kGy. The polymers thus formed were stirred for
two hours in a 1:1 mixture of distilled water and ethanol to remove remaining soluble
fractions, and were then dried in an oven at 40 ºC (Singh, & Vashistha, 2008).
Cross-linking of gums requires availability of active functional groups in their basic
structure. Hence, gums such as guar gum, cashew gum or sterculia gums that possess
free alcoholic and/or carboxylic units seem to be a good choice for modification by
cross-linking. However, it is essential to investigate the vulnerability of the cross-
linking to different pH in order to use the modified molecule for site specific
delivery.
2.7.3. Mechanism of cross-linking: modification of gums.
Natural gums are generally soluble in water. This is due to the presence of an
excessive number of –OH moieties which form hydrogen bonds with water
molecules. Hence, these natural gums cannot be used for controlling drug release.
Moreover, the –OH moieties are unable to form strong ionic interactions with counter
ions. Therefore, these gums need to be modified by derivatisation. A wide variety of
functional groups can be attached to natural gums to make them more suitable for
controlling the release of drugs from dosage forms. For example, attachment of
carboxyl groups, carboxymethyl groups, polyacrylamide groups, phosphate groups
etc, have all been extensively investigated for such purposes.
Interestingly, the properties of cross-linked gum derivatives depend mainly on their
cross-linking density, namely the ratio of moles of cross-linking agent to the moles of
polymer repeating units. Moreover, a critical number of cross-links per chain are
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required to allow the formation of a network. The types of interactions forming the
network depend on the nature of the cross-linker. Therefore, cross-linked gums or
their derivatives can be classified as:
(i) Hybrid polymer networks (HPN) (ii) Semi or full inter-penetrating polymer networks (IPN) (iii) Ionically cross-linked gums or their derivatives (reversible cross-linking)
composed of KG, copolymerised with acrylic acid (AA) and cross-linked by N, N-
methylene-bis-(acrylamide) (MBAAm) were prepared. The influence of various
parameters on the equilibrium swelling ratios of the hydrogels was investigated
(Chen, Liu, & Zhuo, 2005). The results revealed that swelling ratio was inversely
proportional to the content of MBAAm. Also, it was possible to modulate the degree
of swelling of the gels by changing the cross-linking density of the polymer. The
swelling ratio of the gels responded to variation in environmental pH. The results of
degradation tests revealed that the hydrogels retained the enzymatic degradation
character of KG and could be degraded by 52.5% in 5 days using Cellulase E0240.
In-vitro release of 5-aminosalicylic acid (5-ASA) in the presence of Cellulase E0240
in pH 7.4 phosphate buffer at 37°C reached 95.19% after 36 h and was controlled by
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Table 2.20: Pharmaceutical applications of gums in drug delivery
S.No. Natural Gum Model Drug Dosage form
Remarks Reference(s)
A. Guar Gum
1. 97.3% Dexamethasone Tablets 72-82% of Dexamethasone was delivered to colon.
Kenyon et al. (1997)
340 mg per 420 mg tablet (77.19%)
Indomethacin Matrix tablets
In-vitro drug release without rat caecal medium was 29.2% which was increased upto 49.7% and 59.64% with 2% and 4% of rat caecal medium, respectively.
Prasad, Krishnaia, & Satyanarayana (1998)
3. 100 mg coating over 80 mg core tablet (125%)
Indomethacin Tablets In-vitro Cumulative percent drug release with rat caecal medium (2%, 21 h study) was ≤ 20%.
In-vivo Scintigraphy study showed intact tablet in small intestine (2 h), the commencement of disintegration of the coat (4 h), distribution of broken pieces of the tablet in ascending colon, hepatic flexure, transverse colon and splenic flexure (8 h)
In vitro drug release without rat caecal medium was 63.5% which increased upto 82% with Rat caecal medium (4%)
Shyale, Chowdary, & Krishnaiah (2005)
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14. 50% Albendazole and Albendazole β-cyclodextrin
Matrix tablets
In vitro drug release without rat caecal medium was 67.7 %
In-vivo studies healthy human volunteers showed Cmax (916.49 ng/mL) at 12 h
Shyale, Chowdary, Krishnaiah, & Bhat (2006)
15. 150mg coating per 213 mg core tablet (70.42%)
Ondansetron Matrix tablets
In-vitro drug release was found to be 19.8% over 8 h.
After galactomannase enzyme addition(19.6 U/L) the drug release was increased up to 84.90% after 10 h
Demiroz, & Takka (2006)
16. 44% Indomethacin Pellets
(Coatd with
Eudragit FS 30D)
In vitro drug release with GG/ Eudragit FS 30D double coated pellets was found to be 66.56% (After 7 h) which increased up to 100.2 %, when drug release was studied in presence of enzymes.
In-vivo study was carried out in Beagle dogs which showed Cmax=1291.51 ng/ml and Tmax=5.41 h with double coated pellets while Eudragit FS 30D coated pellets showed Cmax=3296.87 ng/ml and Tmax=2.46 h
Ji, Xu, & Wu (2007)
17. 75% Diltiazem Matrix tablets
(coated with
In vitro drug release for uncoated GG formulated tablets when unincubated SCF was used was found to be 60% at end of
Ravi, Mishra, & Kumar (2008)
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double coating of Inulin and shellac)
dissolution study (11 h),which was increased up to 80% with incubated medium
With 2% inulin coating 28% was released after 11 h
B. Guar gum methacrylate conjugates
18. Graft copolymer of GG with acrylamide by crosslinking with glutaraldehyde
(5% W/V)
Verapamil (VRP) and Nifedipine(NFD)
Hydrogel Microspheres
Non-fickion drug release was observed
Soppirnath, & Aminabhavi, (2002)
19. Methacrylic acid-g-Guar gum
(MAA-g-GG)
Metronidazole Tablets In vitro drug release with Eudragit L 100 coated tablets (with MAA-g-GG:Xanthum gum,3:1) was found to be (86.6%).
The Eudragit L 100 coated tablets (with MAA-g-GG:Xanthum gum,1:3) cause maximum retardation in drug release
Mundargi, Patil, Agnihotri, & Aminabhavi (2007)
C. Guar gum-alginate conjugates
20. Guar gum-Alginate combination cross linked with glutaraldehyde
BSA Hydrogels During one step drug release studies (Separate release studies at pH 1.2 and 7.4 for 10 h) only 20 % BSA released after 10 h at pH 1.2. While two step drug release studies (pH 1.2 for 2 h followed by study
George, & Abraham (2007)
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at pH 7.4 up to 10 h) showed 94% BSA was released after 10
D. Crosslinked Guar Gum
I. Crosslinking with glutaraldehyde
21. Indomethacin, Sodium salicylate and Budesonide
Discs In-vitro drug release studies showed that Sodium salicylate shows complete drug release within 120 min. while Indomethcin and Budesonide showed negligible drug release for 10 h, which enhanced after galactomannase addition.
Kabir, Yagen, Penhasi, & Rubinstein (1998)
22. Metronidazole Microsphere In vitro drug release without rat caecal medium was 31.23% which was increased with Rat caecal medium (2% and 4%) upto 47.72% and 61.65% respectively which further increased up to 59.35% and 76.72% after enzyme induction.
Chourasia, & Jain (2004)
23. Methotraxate Microsphere In vitro drug release Without rat caecal medium was 38.9% which was icreased with Rat ceacal medium(6%) upto 73.20% which further increased up to 91% after enzyme induction
Chourasia et al. (2006)
24. Ibuprofen Hydrogel Discs
Cumulative percent in vitro drug release( 2 h SGF , 3 H SIF) was found to be 2-5%
Das, Wadhwa, & Srivastava (2006)
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II Crosslinked with tri sodium trimetaphosphate (STMP)
25. Hydrocortisone Hydrogels Increase in degree of cross linking caused decrease in extent of degradation during In-vitro drug release in presence of rat ceacal medium.
Kabir, Yagen, Penhasi, & Rubinstein (2000a)
E. Xanthan gum
26. Caffeine,
Indomethacin,Sodium Indomethacin
Matrix tablets
Within physiologic ionic strength range the swelling of XG matrix tablets shows a reciprocal relation of In-vitro release with salt concentration.
Drug release was influenced by ionic strength and buffer conc.
Drug release depends on swelling behavior.
Talukdar, & Kinget (1995)
F. Xanthan gum derivatives
27. Combination with Konjac glucomannan,KGM
(20%TWG)
Cimetidine
Matrix tablets
XG shows more In-vitro drug release than konjac glucomannan
Β-mannase accelerates drug release from matrix tablets prepared by Konjac glucomannan but no effect on tablets prepared by XG.
Matrix tablets with a single polysaccharide (either XG or KGM) could not retard drug release from tablets effectively while XG: KGM complex does.
Jiangyang, Wang, Liu, & He (2008)
28. XG:GG 5-FU Matrix In-vitro drug release was found to be 42.6% which was increased
Sinha, Mittal, Bhutani, &
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(10:20) tablets upto 67.2% with 2% and 80.34% with 4% rat caecal medium.
Kumaria (2004)
29. Combination with Konjac glucomannan (both American and Japanese varities)
Diltiazem Tablets In vitro drug releasewith Japanese KGM drug release was complete within 24 h in the presence of β-mannase. There was a smaller effect on release from formulation of American KGM.
Manceñido, Landin, Lacik, & Pacheco (2008)
30. Xanthum gum:Boswellia gum (3:1) with 300 mg total coat weight AND Boswellia gum:HPMC (2:3) with 275 mg total coat weight
5-FU Compressed coated tablets
In-vitro drug release was found to be 80.2% which was increased upto 98.22% with 2% rat caecal medium
Studies also showed that XG play a major role in retardation of drug release
Sinha, Singh, Singh, & Binge (2007)
G. Khaya gum and albizia gum
31. Khaya gum (300mg) and Albizia gum (400mg)
Paracetamol and Indomethacin
Tablets In vitro drug release (After 12 h) of coated with khaya gum(400 mg) was 33.09% for Indomethacin and 36.10% for Paracetamol.
In vitro drug release with rat caecal media (of Indomethacine only) of tablets coated with Khaya gum (400mg) was 98.68% while albizia gum (400mg) coated tablets
Odeku, & Fell,
(2005)
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showed 94.34% drug release
Tablets coated with Khaya:Albizia(1:1) mixture(400mg) showed 97.34% drug release
H. Crosslinked gellam gum
32. A.(I)With Calcium or Deacylated gellam gum crosslinked with calcium
Azathiopurine
Beads (Coated with Eudragit S 100)
Uncoated tablets showed 32.27% In-vitro drug release at pH 7.4 with galactomannase as compared to coated tablets (28%)
Singh, Trombetta, & Kim (2004); Singh, & Kim (2007)
I. Locust bean gum
33. Locust bean gum:Chitosan
(4:1)
Mesalazine Compression coated tablets
4:1 ratio showed best In-vitro drug release.
In-vivo study (Human):-Cmax=28.25µg/ml,Tmax=16 h,AUC =498.62 µg.h/ml
Raghavan, Muthulingam, Josephine, Jenita, & Ravi (2002)
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the swelling and degradation of the hydrogels. The results suggested that although,
KG was biodegradable, safe and water soluble, it could not prevent drug release due to
its sensitivity to large variations in pH encountered in the gastrointestinal tract. On the
other hand, poly(acrylic acid) is pH dependent, but is a non-biodegradable polymer.
Therefore, combining KG and poly(acrylic acid) was envisaged for combining the
with a mixture of xanthum gum and guar gum. It was found that the XG:GG mixture
(10:20) coated tablets were able to deliver drug to the colon.
Gellan gum has been investigated as a possible carrier for colonic drug delivery.
Singh, & Kim (2007) investigated potential interactions among a model drug
(azathioprine; AZA), polymers, and a divalent metal ion, which were utilised for
developing a novel multiparticulate formulation for colonic drug delivery. The authors
prepared beads by ionotropic gelation of deacylated gellan gum (DGG) in the
presence of Ca2+ ions, followed by coating with Eudragit® S-100. The results of FT-IR
studies suggested interactions of DGG with AZA and Eudragit® S-100, and provided
evidence for interactions of AZA and DGG with Ca2+ ions, which was also supported
by results of DSC studies.
Gums are abundantly found in nature. They are cheaper than the synthetic polymers
available for various purposes. In addition, they are well tolerated by the human body
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because they are easily degraded to monosaccharides by colonic bacteria. However,
the highly swellable nature of their putative form often restricts their use for delivering
drugs to distal parts of the gastrointestinal tract.
The present discussion revealed different approaches that have been investigated for
modifying the properties of gums. The modified gums were observed to be useful for
preparing various dosage forms with modified drug release profiles. Unlike the dosage
forms prepared using synthetic polymers, the dosage forms prepared with modified
gums do not suffer from the disadvantage of incomplete drug release. This is due to
their susceptibility to degradation by colonic microflora.
Certain modifications like carboxymethylation and carbomoylethylation by
replacement of few free-OH groups increase the aqueous solubility of gums. Hence,
the resultant moiety is not suitable for delaying the drug release. Therefore, these
groups need to be cross-linked with the oppositely charged anions. These cross-linked
structures are resistant to dissociation in acidic pH but slowly degrade in the intestine,
thus providing sustained release of drugs from dosage forms during the transit in the
gastrointestinal tract. Similarly, phosphorylation of gums with sodium metaphosphate
is reported to be useful in designing dosage forms for colonic drug release.
However, the degree of substitution is the main concern in almost all types of
modifications. A low degree of substitution leads to less cross-linking density, which
in turn results in premature release of drug in the gastrointestinal tract. Therefore,
gums containing galactomannan are ideally suited for modification since they contain
carboxylic groups, which are more amenable to cross-linking than hydroxyl groups.
The abundance of gums, their economic cost and biodegradability have compelled
formulation scientists to design approaches for making them suitable for modifying
the drug release of dosage forms.
2.8 5-Fluorouracil
5-Fluorouracil (5-FU) has been in use for the treatment of cancer for more than
two decades. It is a fluorinated antimetabolite of uracil (Figure 2.7). It slows tumour
cell growth by inhibiting thymidine formation, thereby inhibiting protein synthesis by
getting
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Figure 2.29:Structure of 5-fluorouracil
incorporated into RNA. The physical properties of 5-FU are summarized in Table
2.21.
Transdermal delivery of 5-FU
It has been found that slow intravenous administration of anti-cancer drugs prolong
their effect and theoretically maximizes their exposure to dividing cells (Chabner et
al., 1996). Similarly, reducing the rate of injection to slow continuous infusion has
been found to decrease the toxic effects of 5-FU. But, the parenteral administration in
the form of continuous infusion entails certain risks and therefore, necessitates
hospitalization and close medical supervision (Chien, 1992). Rapid intravenous
administration gives peak plasma concentration with in minutes and the drug is so
rapidly cleared from the blood that the drug level is undetectable after 2-3h (Chabner
et al., 1996). Availability of 5-FU following oral administration is only 28% due to
high degradation particularly in the liver and intestinal mucosa by the enzyme
dihydropyrimidine dehydrogenase. Therefore, transdermal delivery of 5-FU seems to
be the best mode of systemic delivery so as to obtain maximum effectiveness with
least associated toxicity. Moreover, 5-FU is reported to be stable against skin enzymes
(Sugibayashi et al., 1985) which makes it a good candidate for transdermal delivery.
Furthermore, the literature revealed the use of 5-FU as model polar drug for
evaluating the mechanism of penetration enhancers such as terpenes, azone, fatty
acids, amines, etc. (Goodman and Barry, 1988; Aungst et al., 1990; Williams and
Barry, 1991; Lee et al., 1993; Yamane et al., 1995; Abdullah et al., 1996; Moghimi et
al., 1998).
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The in vitro permeation characteristics of 5-FU and flurbiprofen were investigated
through three layers of the human nail plate. Most of the lipids in the human nail plate
are present in the dorsal and ventral layers. With respect to 5-FU permeation through
each single layer, the permeability coefficient of the intermediate layer was higher
than those of other single layers. The diffusion coefficients of 5-FU and flurbiprofen
in the dorsal layer were lowest through any single layer. Hence, it was suggested that
the human nail plate behaved like a hydrophilic gel membrane rather than a lipophilic
partition membrane and that the upper layer functioned as the main nail barrier to drug
permeation due to its low diffusivity(Kobayashi et al., 1999). Further it was observed
that addition of penetration enhancer in a lotion formulation, Belanyx (containing
urea, propylene glycol) improved the efficacy of a low
concentration of 5-FU (1% w/v) in psoriatic finger nail lesions. However, Belanyx
without enhancer did not increase the efficacy of 5-FU in psoriatic nail dystrophy in
this study population (de Jong et al., 1999).
The effect of volatile oils from Rhozoma Apiniae officinarum, Pericarpium
zanthoxyli, Herbal asari, cineol and ethanol extracts on the percutaneous penetration
of 5-FU was studied. The results suggested that these volatile oils (1%-3% v/v)
enhanced the percutaneous absorption of 5-FU (Shen et al., 2000).
Levy et al. (2001) compared the percutaneous absorption of 3H-labeled fluorouracil
from three fluorouracil (0.5%) formulations incorporated in to a porous microsphere
delivery system with that from a commercially available fluorouracil (5%)
formulation. The flux of 5-FU from microsphere systems was 20 to 40 times greater
than that from the conventional formulations. Higher percentage of absorbed
fluorouracil was found to be retained in the skin in 24 h after application of these
formulations.
The stratum corneum layer of skin gets partly ablated by an erbium-Yag laser-treated
skin. The permeation of 5-FU was 53-133 fold higher than that across intact skin (Lee
et al., 2002). Electroporation exerted a disruptive influence on the stratum corneum.
However, combining electroporation with erbium: Yag laser led to partial ablation
resulting in enhanced skin permeation of 5-FU (Fang et al., 2004). The systemic
delivery of percutaneously applied 5-FU across athanol-perturbed rat skin treated with
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either 600 µg or 1200 µg beta chloroalanin (beta-CA, an inhibitor of sphigosin
synthesis) was found to be significantly greater as compared to that after oral
administeration or after application of lower percutaneous doses of beta- CA (Gupta et
al., 2004). This suggested that 5-FU permeated through the polar pathway. The
passive permeation of 5-FU was observed to depend upon the pH of the donor
solution. Its permeation was enhanced by approximately 3, 4 and 24-fold,
respectively, when isopropyl myristate, lauryl alcohol and azone were incorporated in
to the donor solution. Azone appeared to be better enhancer for 5-FU, indicating its
permeation from the polar pathway (Singh et al., 2005c).
Table 2.21:The physical properties of 5-FU
Sr. No. Properties Description
1. Emperical Formulae C4H3FN2O2
2. Molecular weight 130.08
3. Appearance, colour and odor
White to practically white, odourless, crystalline powder
4. Melting point 282 °C to 283 °C
5. Log P
(n-octanol/ water)
-2.987
6. Solubility 1 gm in 8 ml water, 170 ml alcohol, 55 ml methanol, insoluble in chloroform, ether and benzene. Soluble in aqueous solutions and solubility increases with increase in pH.
7. Pka 8.1
Colo-rectal delivery of 5-FU
5-Fluorouracil (5-FU)' was synthesized in 1957 and since then has become an
established antineoplastic agent used clinically in the treatment of various human solid
tumors. The biochemical mechanisms of action for 5-FU have been studied
extensively (Cohen et al., 1958; Dannberg et al., 1958) with particular emphasis on
thymidylate synthetase inhibition (Hartmann and Heidelberger, 1961) and
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incorporation of 5-FU into RNA (Fernandes and Bertino, 1980). Metabolic
modulation to enhance either of these two actions has failed to show a causal link with
therapeutic efficacy ((Fernandes and Bertino, 1980; Spiegelman et al., 1980) and the
relative importance of each remains controversial. Neither mechanism excludes an
antitumor effect separate from these antimetabolic actions.
The concept that 5-FU acts primarily as a cytotoxic drug affecting rapidly dividing
cells has lead to the use of high doses that are active against not only tumor cells, but
also cells of the gastrointestinal mucosa and the hematopoietic system (Makinodan, et
al., 1970; Mitchell and DeConti, 1970). It has been assumed that 5-FU is
immunosuppressive because of the inhibitory effects seen at these high doses
(Mitchell and DeConti, 1970). Studies of the effect of 5-FU and other fluorodinated
pyrimidines on the rodent immune response have been conflicting (Santos and Owens,
1964). Merrit and Johnson (1963) demonstrated significant augmentation of the
murine immune response when 5-FUDr (the deoxyriboside of 5-FU) was given before
antigen administration. Conversely, however, 5-FU and 5-FUDr produced
immunosuppression when given after antigen administration. Blomgren et al. (1965)
have demonstrated that delayed hypersensitivity may be augmented by 5-FU. Uy et al.
(1965) failed to show immunosuppression by either 5-FU or 5-FUDr of the mouse
anti-sheep erythrocyte response. Similar lack of immunosuppression has been
demonstrated in rabbits (Sterzl, 1961). The disparate effects of 5-FU on rodent
immune responses can be attributed to differences in dosage and in timing of
administration in relation to antigen stimulation. These factors are often of
criticalimportance in the immune response to any agent.
Although, 5-FU is a widely used antineoplastic agent, the cytotoxicity of 5-FU is not
limited to tumor tissue. Hematopoietic cells and normal epithelial cells of the GI tract
are susceptible to 5-FU-induced cytotoxicity, which produces severe leucopenia and
intestinal toxicity leading to lethal translocation of intestinal microflora (Kucuk et al.,
2005). In addition, because of the short plasma half-life of 10–20 min, high doses have
to be administered repeatedly by IV route to reach therapeutic drug levels (Peters et
al., 1993). Moreover, the clinical use of 5-FU is limited by its GI (stomatitis and
myelotoxicity) toxicity (Fraile et al., 1980). The oral bioavailability in humans is
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reported to be only 28% (Gilman, 1996). The reported severe systemic toxic effects
and very short plasma half-life make this drug particularly suitable for local delivery
at the site by a suitable drug delivery system thus, exposing the diseased tissues in a
continuous and sustained manner (Koole et al., 1998). Colorectal delivery of 5-FU is
expected not only to reduce the systemic side effects, but can also be expected to
provide an effective and safe therapy for colon cancer with reduced dose and duration
of therapy.
Intravenous administration of 5-fluorouracil for colon cancer therapy produces severe
systemic side-effects due to its cytotoxic effect on normal cells. Krishnaiah et al.,
(2002) developed novel tablet formulations for site-specific delivery of 5-fluorouracil
to the colon without the drug being released in the stomach or small intestine using
guar gum as a carrier. Fast-disintegrating 5-fluorouracil core tablets were compression
coated with 60% (FHV-60), 70% (FHV-70) and 80% (FHV-80) of guar gum, and
were subjected to in vitro drug release studies. Guar gum compression-coated tablets
released only 2.5-4% of the 5-fluorouracil in simulated GI fluids. When the
dissolution study was continued in simulated colonic fluids (4% w/v rat caecal content
medium) the compression-coated FHV-60, FHV-70 and FHV-80 tablets released
another 70, 55 and 41% of the 5-fluorouracil respectively. The results of the study
show that compression-coated tablets containing 80% (FHV-80) of guar gum are most
likely to provide targeting of 5-fluorouracil for local action in the colon, since they
released only 2.38% of the drug in the physiological environment of the stomach and
small intestine. In another study Sinha et al (2007) developed colon-specific
compression coated systems of 5-fluorouracil (5-FU) for the treatment of colorectal
cancer using xanthan gum, boswellia gum and hydroxypropyl methylcellulose
(HPMC) as the coating materials. Core tablets containing 50 mg of 5-FU were
prepared by direct compression. The coating of the core tablets was done using
different coat weights (230, 250, 275 and 300 mg) and different ratios (1:2, 2:1, 1:3,
1:7 and 3:4) of boswellia gum and xanthan gum and different ratios (1:1, 1:2, 2:1, and
2:3) of boswellia gum and HPMC. Among the different ratios used for coating with
boswellia:xanthan gum combination, ratio 1:3 gave the best release profile with the
lowest coating weights of 230 mg (7.47 +/- 1.56% in initial 5 h). Further increase in
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the coat weights to 250, 275 and 300 mg led to drug release of 5.63 +/- 0.53%, 5.09
+/- 1.56% and 4.57 +/- 0.88%, respectively, in the initial 5 h and 96.90 +/- 0.66%,
85.05 +/- 1.01% and 80.22 +/- 0.35%, respectively, in 24 h. Increasing the coat
weights to 250, 275 and 300 mg led to drug release of 6.5 +/- 0.27%, 3.70 +/- 2.3%
and 2.99 +/- 0.72%, respectively, in the initial 5 h and 96.90 +/- 0.66%, 85.05 +/-
1.01% and 80.22 +/- 0.35%, respectively, in 24 h. In-vitro studies were further carried
out in the presence of 2% w/v rat caecal contents, which led to complete release of the
drug from the tablets. Therefore, this study lays a basis for use of compression coating
of 5-FU as a tool for delaying the release of the drug, which ensures better clinical
management of the disease.
The distribution in the gastrointestinal (GI) tract of Eudragit S-100 encapsulated
colon-specific sodium alginate microspheres containing 5-fluorouracil (5-FU) in rats,
were determined and compared with a control immediate-release (IR) formulation of
5-FU. (Rahman et al., 2008). 5-FU was distributed predominantly in the upper GI tract
from the IR formulation but was distributed primarily to the lower part of the GI tract
from the microsphere formulation. No drug was released in the stomach and intestinal
regions from the colon-specific microspheres. Significantly, a high concentration of
the active drug was achieved in colonic tissues from the colon-specific microspheres
(P < 0.001), which was higher than the IC50 required to halt the growth of and/or kill
colon cancer cells. Colon cancer was induced in rats by subcutaneous injection of 1,2-
dimethylhydrazine (40 mg kg (-1)) for 10 weeks. The tumours induced were non-
invasive adenocarcinomas and were in Duke's stage A. The 5-FU formulations were
administered for 4 weeks after tumour induction. Non-significant reductions in tumour
volume and multiplicity were observed in animals given the colon-specific
microspheres. Enhanced levels of liver enzymes (SGOT, SGPT and alkaline
phosphatase) were found in animals given the IR formulation of 5-FU, and values
differed significantly (P < 0.001) from those in animals treated with the colon-specific
microspheres. Elevated levels of serum albumin and creatinine, and leucocytopenia
and thrombocytopenia were observed in the animals given the IR formulation. In
summary, Eudragit S-100 coated alginate microspheres delivered 5-FU to colonic
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tissues, with reduced systemic side-effects. A long-term dosing study is required to
ascertain the therapeutic benefits.
Paharia et al., (2007) prepare and evaluate Eudragit-coated pectin microspheres for
colon targeting of 5-fluorouracil (FU). Microspheres prepared by using drug:polymer
ratio 1:4, stirring speed 1000 rpm, and 1.25% wt/vol concentration of emulsifying
agent were selected as an optimized formulation. The in vitro drug release study of
optimized formulation was also performed in simulated colonic fluid in the presence
of 2% rat cecal content. Organ distribution study in albino rats was performed to
establish the targeting potential of optimized formulation in the colon. The release
profile of FU from Eudragit-coated pectin microspheres was pH dependent. In acidic
medium, the release rate was much slower; however, the drug was released quickly at
pH 7.4. It is concluded from the present investigation that Eudragit-coated pectin
microspheres are promising controlled release carriers for colon-targeted delivery of
FU.
In another study, Dev et al (2011) statistically optimize a colon specific formulation of
5-Fluorouracil for the treatment of colon cancer. A 32 full factorial design was used
for optimization. Drug release studies were carried out using change over media [pH
1.2, 7.4 and 6.5 in presence of 4% (w/v) rat caecal contents]. The optimized
formulation consisting of pectin (66.67%, w/w) and starch paste (15%, w/w) released
negligible amount of drug at pH 1.2 and pH 7.4 whereas significant (p < 0.05) drug
release was observed at pH 6.5 in presence of 4% (w/v) rat caecal contents.
Roentgenographic studies corroborated the in vitro observations, thus providing the
“proof of concept”. Pharmacokinetic studies revealed significant reduction in systemic
exposure and cytotoxicity studies demonstrated enhanced cellular uptake of drug by
the developed formulation. Shelf life of the formulation was found to be 2.83 years.
The results of the study established pectin-based coated matrix tablet to be a
promising system for the colon specific delivery of 5-FU so as to treat colon