Post on 02-Apr-2018
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ABSTRACT
World Health Organization reported cancer to be leading cause of death that accounted for
7.6 million deaths worldwide in 2008, which is about 13% of all deaths. Out of this colorectal
cancer caused 610,000 deaths. Multiple factors are associated with the development of
colorectal cancer, including acquired and inherited genetic susceptibility, environmental
elements, and lifestyle choices.Chronic ulcerative colitis, particularly when it involves the
entire large intestine, predisposes individuals to colorectal cancer at a rate that is 4 to 20 fold
greater than average.
Regular use ofnonsteroidal anti-inflammatory drugs is associated with a reduced risk of
colorectal cancer. These drugs exert their protective effects by inhibition of cyclooxygenase-2
(COX-2) and free radical formation. COX-2 overexpression is seen in precancerous and
cancerous lesions in the colon and is associated with a decrease in colon cancer cell
apoptosis, as well as enhanced production of angiogenesis-promoting factors. Inhibition of
COX by NSAIDs, aspirin, and coxibs restores apoptosis and decrease expression of
proangiogenic factors. Microspheres of valdecoxib, a cyclogenase-2 enzyme inhibitor were
prepared in mucoadhesive polymers viz. sodium alginate or chitosan and were film coated
with pH sensitive polymer Eudragit S100. The microspheres were characterized by Fourier
Transform Infrared Spectroscopy (FTIR), X-ray Diffraction(XRD) and Differential Scanning
Calorimetry(DSC) and were evaluated for particle size, drug load, in vitro drug release,
release kinetics, accelerated stability and extent of mucoadhesion. The coated microspheres
released the drug at pH 7.4, the putative parameters for colonic delivery. Microspheres
pretreated with phosphate buffer pH 7.4 for 30 minutes, when applied to mucosal surface of
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freshly excised goat colon, showed mucoadhesion. To ascertain the effect of valdecoxib on
the viability of Caco-2 cells, the3-(4,5-dimethylthiazol-2yl) 2,5-diphenyltetrazolium
bromide) (MTT) test was conducted using both valdecoxib and coated microspheres. In both
cases, the percentage dehydrogenase activity indicated lack of toxicity against Caco-2 cells in
the tested concentration range. Drug transport studies of both, the drug as well as well as the
coated microspheres in buffers of pH 6 and 7.4 across Caco-2 cell monolayers were
conducted. The microspheres were found to exhibit slower and delayed drug release and
lower intracellular concentration of valdecoxib.
In order to provide patients with better schedules of treatment, several oral anticancer agents
have been developed and evaluated in colorectal cancer. The main dose limiting factor for
cytotoxic drugs is the tolerance of normal tissues. Systemically administered drugs will
always cause damage to normal healthy tissues, although this varies between different agents.
Therefore, it is not possible to simply use higher drug doses to achieve clinically useful
destruction of the cells comprising a solid tumor.Direct administration of cytotoxic agents
into the environment of tumor has the potential to increase target cell exposure, while at the
same time decreasing exposure of normal tissues. This principle has been widely applied by
administering cytotoxic drugs either directly into the tumor or into the body cavities, such as
the peritoneal or pleural space. Camptothecin (CPT), a potent antitumor drug, exhibits poor
aqueous solubility andrapid conversion fromthe pharmacologically active lactone form to
inactive carboxylate form at physiological pH.Solid dispersion of camptothecin (CPT) in
Soluplus , an amphiphilic polymeric solubilizer, was prepared to increase the aqueous
solubility of CPT and the resultant solid dispersion along with citric acid was formulated as
hard gelatin capsules that were subsequently coated with Eudragit S100 polymer for colonic
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delivery.FTIR spectrum of the solid dispersion confirmed the presence of CPT. XRD
revealed semi-crystalline nature of solid dispersion having crystalline drug embedded in
amorphous polymer with marked reduction of crystallinity. DSC indicated sharp melting
endotherms of CPT at 259.070
and 268.580
C respectively, against a depressed broad
endotherm of solid dispersion at 257.47 0Cprobably due to the dilution effect of amorphous
polymer,as the solid dispersion contained 24.42% drug.The solubility of the drug was found
to increase almost 40 times in the presence of Soluplus and around 75 times in solid
dispersion. The capsulesshowed no drug release in 0.01N HCl but released 86.4% drug in
lactone form in phosphate buffer (pH 7.4) and the result appears to be due to citric acid-
induced lowering of pH of buffer from 7.4 to 6.0. Thus the presence of citric acid in the
formulation led to stabilization of the drug in its pharmacologically active lactone form.
Cytotoxicity studies conducted with the formulation of solid dispersion with citric acid,
utilizing MTT test on Caco-2 cells, confirmed the cytotoxic nature of theformulation.
For the treatment of acute attack of inflammatory bowel disease, glucocorticosteroids are
almost invariably used and given by mouth. The characteristic profile of glucocorticosteroids
when used for the treatment of these diseases is a high anti-inflammatory effect at the place
of application. Major disadvantage of steroids, when given orally is the extensive first pass
metabolism and hence sub therapeutic concentrations in the blood.First pass metabolism is
the fundamental reason for the safe use of potent topical glucocorticoids in IBD
conditions.Major representatives of the class are budesonide, fluticasone propionate,
flunisolide etc. Inclusion complex of fluticasone propionate with hydroxypropyl
betacyclodextrinwere prepared by solvent evaporation and subsequently the granules of the
inclusion complex were coated with Eudragit S100, in order to achieve colon targeting.
Inclusion complex was characterized by FTIR, XRD and DSC studies.The drug was found to
be present in amorphous form, when included in HPCD cavities. Furthermore, intrinsic
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dissolution of the drug was found to increase by ~ 18 times. In vitro drug release profile of
coated granules exhibited no drug release in 0.01 N HCl as dissolution medium, indicating
gastro-resistance of the drug granules. However 92% of the drug was released in 120
minutes, when phosphate buffer (pH7.4) was used as dissolution medium. The drug transport
studies on rat colon using modified Ussing chamber led to more drug transport and
concentration in target tissue, when presented as inclusion complex.