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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.