Potential application of Colonic drug delivery system in prevention and treatment of Colorectal Cancer

 

Mudassir Ansari, M. Pharma;1 Kavita Singh, M. Pharma, Ph.D.*

1 Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’s NMIMS University, Mumbai, India.

1 Corresponding Author: Dr. Kavita Singh, Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’s NMIMS University, Mumbai, India.

1 Corresponding author’s email: kavita.singh@nmims.edu

 

ARTICLE HISTORY

Received On:

Final Revision Revised On:

Accepted On:

17 July 2021

05 August 2021

15 August 2021

DOI

10.53049/tjopam.2021.v001i03.011

 

 

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer related deaths in USA. The current regimen used to treat colorectal cancer has many side effects and have higher drug distribution in other tissues. Physical activity and diet play major role in prevention of Colon cancer which is briefly discussed in this paper. Colon targeted drug delivery system (CoDDS) is found to be a promising approach to target the drug specifically to colon. This review provides the description of various colon targeted approaches that can be used to treat CRC. Factors to be consider while designing CoDDS include pH of GIT, Transit time of GI tract and Microbiota of colon. This review will discuss the staging and standard treatments modalities for CRC.

 

Keywords: Colorectal cancer, pH sensitive system, microbial triggered system, pH and microbial triggered system, pH and time dependent system, bioadhesive system


1.0        INTRODUCTION

Colorectal cancer (CRC) is the third leading cancer diagnosed all over the world when both men and women are considered 1,2,3. According to American Cancer Society, in USA alone the number of colorectal cancer diagnosed in 2014 was 136,830 1,4,5. Colorectal cancer constitutes 10% of all cancers with a slightly higher risk of occurrence in men then in women 3,4. As far as death rates are concerned, in USA, colorectal cancer is the second highest cause of cancer related deaths when both men and women are combined and third highest when both the sexes are considered separately 1,3,6 . In 2014, deaths due to colorectal cancer in USA were around 50,310 while in 2015 the number of reported deaths was 49,700 1,4,5. There was a major decline in the mortality rate of CRC patient in 2015 as compared to its previous year which is mainly attributed to the advancement and awareness of colorectal cancer screening and treatment 6. A study states that Indians are also at a higher risk of colorectal cancer especially those who have migrated to USA and UK mainly due to change in the dietary habits and lifestyles 1. Colorectal cancer mainly affects the people at the median age of 70 years 5,6 .

The major risk factor for CRC is the development of benign adenomatous polyps (adenomas) a pre-cancerous lesion which if not treated can finally result in CRC. Transformation of adenomatous polyps to adenocarcinoma is a result of multistep genetic and epigenetic processes. Its takes around 10 to 15 years for the polyps to develop into cancer 1,3,7–12. The growth and spread of colorectal cancer adopt a systematic fashion, the tumor starts from the mucosal lining, if not treated properly propagates into the wall of colon and rectum draining in to the blood and lymph vessels. Thereafter, it starts metastasizing to the lymph node and distant organs such as liver, lungs, ovary etc 1,3,4. Over the past few years, ample of fruitful research was carried out for the treatment of CRC probing epigenetic therapy. This novel path has shown promise in the treatment and prevention of CRC.

Colon targeted drug delivery system (CoDDS) has gained remarkable progress in recent years aimed at treating local complications including Colorectal cancer, Chron’s disease, Ulcerative colitis etc where the conventional dosage form is not able to deliver the drug in required concentrations. CoDDS is not only confined to delivering the drugs locally but it is also used for the systemic delivery of proteins, ant diabetic drugs, antiasthmatic drugs. CoDDS have also been explored for the chronotherapy of various diseases including rheumatoid arthritis, angina pectoris, nocturnal asthma etc 1,13–16. The concept and aim of CoDDS is to deliver the drugs safely to the colon by protecting (in terms of drug release, absorption and enzymatic degradation) it from the upper GIT including stomach and small intestine 16–19. Drugs can be targeted to the colon either rectally or orally but the latter is always preferred due to high variability as far as drug distribution is concerned, thus targeting specific sites of colon is a drug delivery challenge 1,6,14,15,19. Patient compliance is also a matter of concern when drug is administered rectally 15. Moreover, oral drug delivery constitutes 50% of the total delivery systems in the market and mostly preferred due to patient compliance and ease of manufacturing 3,20,17. This review aims to explore the pathophysiology and treatment of CRC with an aim to discuss the formulation strategies that have been adopted for targeting drugs to the colon for the treatment and prevention of colorectal cancer.

2.   PATHOPHYSIOLOGY OF COLORECTAL CANCER

The exact pathophysiology of CRC is still unknown. An ample amount of research is carried at molecular level in order to understand the genetic involvement of colorectal cancer. Innumerable genes have been identified which plays a direct or indirect role in the development of CRC. These genes are divided into tumor suppressor gene and oncogene. Colorectal cancer is mainly caused due to the mutation happening in these gene. These mutations can be inherited or acquired in a patient’s life 3. The overall role of these gene in the development and progression of CRC is described in Table 1.

Table 1. Involvement of various genes in the pathophysiology of colorectal cancer (Modified from Ref 3)

Categories of gene

Genetic defects

Genes

Pathophysiology

 

Tumor suppressor gene

 

 

 

 

Instability

in chromosomes

APC

Somatic mutation of APC leading to sporadic CRC, germ line mutation of APC causes FAP. It also activates Wnt signalling due to the failure in degrading beta catenin oncoprotein

TP53

Germ line mutation

SMAD4

Germ line mutation

PTEN

Germ line mutation that causes the activation of PI3K signalling pathway

Defects in DNA mismatch repair system

MLH1,

MSH2,

MSH6, MYH

Germ-line mutation causes accumulation of oncogenic mutations and leads to tumour suppressor loss

Aberrant

DNA methylation

MLH1

Hyper-methylation of

CpG islands causes silencing of the promoter region of the genes in mismatch-repair system

 

Oncogenes

 

Defects in DNA mismatch repair system

RAS, BRAF

Activates MAP kinase signalling pathway

Abbreviations: APC, Adenomatous polyposis coli; TP53, Tumor protein 53; SMAD4, Mothers against decapentaplegic homolog 4; PTEN, Phosphatase and tensin homolog; PI3K, Phosphatidylinositol-4,5-bisphosphate 3-kinase; MLH1, MutL homolog 1; MSH2, MutS protein homolog 2; MSH6, MutS protein homolog 6; MYH, MutY Homolog; RAF, RAF proto-oncogene; BRAF, B-RAF proto-oncogene.

3.       TREATMENT OF COLORECTAL CANCER

There are six standard treatments for the management of colorectal cancer. The treatments include 19 surgery, radiation therapy, chemotherapy, targeted therapy, radiofrequency ablation, cryosurgery. Each of these treatments are used depending upon the stages of colorectal cancer.

3.1. Surgery

Surgery is the primary treatment when the tumor is not metastasized throughout the body and it is the only treatment in stage 0 and stage 1 colon cancer 5. Depending upon the severity of cancer, surgery can be of various types as follows:

3.1.1.     Local expurgation

In this type of surgery, the cancer is excised from the abdominal wall without invasion. In order to perform this, a long tubing holding camera and cutting tool is used. This tube is inserted into the colon and the portion of the colon where the cancer resides is removed along with some nearby tissues. The term polypectomy is used when the cancer is detached in the form of polyps. This procedure is implemented when the tumor is in the initial stage and can be easily treated without resection 6,21.

3.1.2.     Incision of the colon

Incision is performed when the tumor has grown in each of the layers of colon. This involves an invasive procedure whereby the affected part of the colon is cut off with some nearby healthy tissues and the two healthy ends of the resected colon is sewed. This procedure is termed as partial colectomy, hemicolectomy or segmental resection. In some cases, it is not possible to sew both the healthy ends, in such circumstances colostomy is done where a small hole is made outside the body to which the bag is attached for the collection of waste. Nearby lymph nodes are also removed and tested for the presence of trace number of cancers. Total colectomy is mainly done when the person is suffering from familial adenomatous polyposis where the whole colon containing polyps is removed 22,23.

3.2.     Radiation therapy

Radiation therapy is mainly given after surgery to ensure the killing of tumor cells in other parts of the body where the cancer has spread. It is also used for the patients who are not liable enough of performing surgery. It uses X rays of high energy and other types of radiation depending upon the stage of colon cancer. Radiation therapies are given in two form viz. external beam radiation and internal beam radiation. In external beam radiation the radiations are provided outside of the body by using machines while internal beam radiation utilizes radioactive material in the form of pellet or attached to the tubes and are inserted towards the tumor site 5,22.

3.3.     Ablation

This technique involves the destroying of tumor cells without any kind of surgical intervention. Ablation are of two types viz. radiofrequency ablation and ethanolic ablation. Radiofrequency ablation involves the usage of a very thin probe which is introduced through the skin t the tumor site such that it passes into the tumor. After this, a high frequency radio waves are passed which kills the tumor by heating it. This process is carried out using local anaesthesia. Sometimes, an incision has to be made in the abdomen from where the probe is inserted and destroys the tumor cells. Ethanolic ablation involves the injection of concentrated ethanol at the tumor site so as to directly destroy the tumor cells 5,22.

3.4.     Cryotherapy

Cryotherapy is a technique that can kill the tumor cells by freezing it with the help of a thin metal probe. Ultrasound is used to guide the probe through the skin to reach the tumor cells. This is followed by passing a very cold gas, which can freeze the tumor leading to destruction of the cancer cells. It is commonly addressed as Cryosurgery, which includes open cryosurgery, laparoscopic cryosurgery, and percutaneous cryoablation 22.

3.5.     Chemotherapy

Chemotherapy is defined as the use of anti-cancer drug to kill tumor cells or stop its growth and propagation. Chemotherapy is classified into systemic chemotherapy and regional chemotherapy. Systemic chemotherapy involves the administration of anti-cancer drug directly into the blood stream either orally or through injections. In regional chemotherapy the drugs are incorporated directly into the organs where the chances of metastasis are higher, this prevents the encounter of drugs to other parts of the body and thus minimizing the side effect. Hepatic artery infusion is one of the examples of regional chemotherapy whereby the drug is administered into the hepatic artery through infusion, the blood flow present in the hepatic artery will direct the drug only to the liver thus preventing the exposure to other organs. Depending upon the stages of colon cancer, chemo can be administered before and after surgery. When given before surgery it is called as neoadjuvant chemotherapy which mainly deals with decreasing the size of tumor so that the surgery can be done easily. Adjuvant chemotherapy involves the administration of drug after surgery to ward off the remaining tumor cells if at all present in the body. Chemotherapy is also given when cancer has metastasized so as to increase the survival rate of patient by decreasing the size of tumor. The side effects of chemotherapy include hand foot syndrome, neuropathy, increase chances of infection etc 5,6,22.

3.6.     Targeted therapy

Targeted therapy involves the usage of biologics to specifically attack the tumor cells without harming others. It can be given alone or along with chemotherapy when chemotherapy fails to show its inhibitory effect on cancer cells. Targeted therapy delivers drug directly to the colon, this increases drug concentration in the colonic tissue which ultimately leads to reduction of doses. This therapy mainly involves the usage of monoclonal antibodies and angiogenesis inhibitor to circumvent the tumor cells. The main advantage of targeted therapy over chemotherapy is reduction in side effects due to its specificity 5,22. Drugs used in the treatment of CRC include 5-FU, leucovorin calcium, capecitabine, irinotecan hydrochloride, oxaliplatin, regorafenib, trifluridine, tipiracil hydrochloride, ziv-aflibercept, bevacizumab, cetuximab, ramucirumab, panitumumab. Combination therapy for the treatment of colorectal cancer are CAPOX- Capecitabine and oxaliplatin, FOLFIRI- 5-FU, leucovorin, and irinotecan, FOLFIRI-BEVACIZUMAB- 5-FU, leucovorin, irinotecan and bevacizumab, FOLFIRI-CETUXIMAB- 5-FU, leucovorin, irinotecan and cetuximab, FOLFOX- 5-FU, leucovorin, and oxaliplatin, FU-LV- 5-FU and leucovorin, XELIRI- Irinotecan and capecitabine, XELOX- Capecitabine and oxaliplatin, FOLFOXIRI- Leucovorin, 5-FU, oxaliplatin, and irinotecan 24.

4.   CHEMOPREVENTION OF COLON CANCER

Chemoprevention is defined as the treatment of precancerous lesions by using dietary compounds and/or synthetic substances so as to reverse, halt or retard the process of carcinogenesis, and to enhance the biological protective mechanisms that will lead to genomic conformity 25–27. Chemoprevention is the best approach to deal with malignancy because cancer treatments decrease the life quality of patients along with an ample of side effects associated with it along with a horrendous cost of treatment 28–30. The overall mechanism of colonic chemoprevention involves the inhibition of alteration at genetic and epigenetic levels that leads to colon carcinogenesis. Some of the mechanisms comprises the activation of DNA repair machinery and apoptotic pathways, inhibition of uptake pathways to retard the uptake of carcinogens by cells, modulation of polyamine metabolisms, growth factors, immune response, hormonal activity and signal transduction 25,26.

The development of colon cancer is not a one step process involving single gene alterations, rather it involves a series of pre malignant lesions with a huge horde of genetic variations. Thus, an ample of changes at the molecular level transform the normal cells into a malignant lesion. Therefore, chemoprevention can be better achieved by targeting these changes and thus protecting the transformation of normal epithelia to colon carcinoma 26,28,29 (Fig. 1). Report suggests that 50% of neoplasm can be prevented by adopting primary and secondary strategies. These strategies are as follows: 26,31–33

4.1.     Physical activity

Studies proposed that regular physical activity is linked with the protection of colorectal cancer. A meta-analysis of 21 studies shows a marked reduction of 27% of getting colon cancer both in the proximal and distant part of colon when the individual who are least active are compared to the one who is most.

4.2.     Diet

Studies on chemoprevention shows a remarkable effect of dietary factors on the prevention of colon cancer. Some of which include folate, omega 3, calcium, vitamins, dietary fibers etc.

4.2.1.     Fruits and vegetables

In an observational cohort study, a comparison was made between individuals having less than 1.5 servings of fruits and vegetables per day with individuals having more than 2.5 servings. Result shows a reduce risk of colon cancer in individuals having more than 2.5 servings while there is no risk reduction in individuals having less than 1.5 servings. Another study suggested the reduction in the risk of colon cancer if the daily consumption of fruits and vegetables is more than 800 g.

4.2.2.     Dietary fibres

Dietary fibers adsorb carcinogens present in feces, modulate bile acid metabolism, enhances short-chain fatty acids production and thus reducing the risk of colon cancer.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


Fig. 1.  Adenoma carcinoma sequence and the target for chemoprevention

 

4.2.3.     Vitamin B

A deficiency of folate increases the risk of colon cancer by causing the mutation of p53 gene. Long term folate intake of 800 μg/dl have been noticed to suppress the risk associated with colon cancer.

4.2.4.     Omega 3

Omega 3 had been proven to play a role in the prevention of colon cancer.  Studies have shown that the consumption of fish is linked to the reduction of colon cancer risk by 12%. The best report is from randomized trial which shows a marked reduction in the occurrence of adenomas with omega-3 in patient suffering from familial adenomatous polyposis.

4.3.     Drugs

Many drugs have been tested from the past decades to prevent colon cancer 25,26,27,31,34,33. These drugs are well described in Fig. 1 and Table 2.

Table 2. List of chemo preventive agents in CRC

Target

Class of drug

Mechanisms

COX2

NSAID

Inhibition of COX.

Cyclooxygenase-independent

pathway.

PPAR- Y

PPAR-Y ligands

Cellular proliferation.

Regulation of inflammatory cytokine.

Ornithine decarboxylase

a-Difluoromethylornithine

Blockade of polyamine synthesis.

Inhibition of ornithine decarboxylase.

S-adenosyl methionine

decarboxylase

Folate

Metabolism of purine and thymidine

for DNA and RNA synthesis.

S-adenosylmethionine (SAM)

formation; methylation maintenance.

Bile acids

Calcium

Inhibition of proliferation. Induction of cell differentiation. Binding of bile and fatty acid.

Vitamin D receptor

Vitamin D

Growth inhibition. Elevation of cellular differentiation.

Bile acids

Inulin

Enhanced calcium absorption.

Direct & indirect effects on colorectal epithelium.

Farnesyl-transferase

Farnesyl-transferase

inhibitors (FTIs)

Induction of apoptosis in tumor cells. Ras activation reversal.

Epidermal growth

factor receptor

EKB-569

Inhibition of epidermal growth factor receptor kinase.

Tyrosine kinase

STI-571

Inhibition of Bcr-Abl tyrosine kinase.

Cyclin-dependent kinase

CDK inhibitors

Cell cycle control.

Matrix metalloproteinase

MMP inhibitors

Basement membrane integrity.

p53

Wild-type p53

Apoptosis with p53 mutation.

iNOS and COX2

Resveratrol, Pterostilbene

Epigenetic modulation.

Abbreviations:

COX, Cyclo-oxygenase; PPAR-Y, Peroxisome proliferator-activated receptor gamma; CDK, Cyclin dependent kinase; MMP, Matrix metalloproteinase; iNOS, Induce nitric oxide synthase.

5.   COLON TARGETED MULTIPARTICULATE DRUG DELIVERY SYSTEM

Multiparticulate drug delivery system (MDDS) involves the usage of pellets, beads, granules, microsphere, spheroids, mini tabs, microparticles and nanoparticles. MDDS having a particle size of more than 200 μm have a very low transit time and also due to ease in the uptake of micron and submicron particles by inflamed cells a multiparticulate approach is predictable to give enhanced pharmacological effects in the colon. In comparison to single unit system, MDDS have several advantages which comprises of easy passage of the system through the GIT owing to less variability between subjects, uniform dispersion throughout the GIT thus causing uniform absorption and enhanced bioavailability, reduction in systemic toxicity due to prevention of dose dumping, decrease of local irritation, estimation of gastric emptying 35, 36.

6.          FACTORS TO BE CONSIDERED IN DESIGNING COLON TARGETED DRUG DELIVERY SYSTEMS

The factors that are considered for designing CoDDS includes:

6.1.     pH of GIT

This is one of the most important factors which is to be considered in designing CoDDS. This is the primary approach utilizes gastrointestinal pH in delivering drugs to the colon. pH of GI tract is highly variable between individuals and also affected by fed and fasted state. Disease of GIT have a greater impact on pH especially IBD which decreases the pH of the colon to 5.3. The details of pH in every segment of GIT are given in Table 3 6,13,17.

Table 3. pH of various segments of gastrointestinal tract

Regions of GIT

pH

Stomach

1.5 – 3 (fasted state)

4 – 5 (fed state)

Small intestine

Duodenum

 

Jejunum

Ileum

 

3 – 6 (fasted state)

1.7 – 4.3 (fed state)

5.4

7 – 8

Cecum

5.5 – 7

Colon

Ascending colon

Transverse colon

Descending colon

Sigmoid colon

 

6.4

6.6

7

7 – 8

Rectum

7 – 8

Anal canal

7 – 8

6.2.     Transit time of GI tract

Like pH, transit time of GIT is highly variable and depends on fed and fasting condition of the subject. Disease also has a great influence on GI transit time e.g., patient suffering from ulcerative colitis and diarrhoea has increased colon transit time than normal. Transit time of gastrointestinal tract also depends upon the dosage form size and density 6,13,15. Transit time of small intestine is independent of the fed and fasting condition 6,15. One of the approaches uses the concept of GI transit time for delivery of drugs to the colon. The transit time is well explained in Table 4 13.

Table 4. Transit time of various segments of GIT

Region of GIT

Transit time (h)

Stomach

< 1 (fasted)

>3 (fed)

Small intestine

3 – 4

Colon

20 – 30

6.3.     Microbiota of colon

There are clusters of bacteria residing in the colon both aerobic and anaerobic that are responsible for various biochemical activities which include metabolism of xenobiotics, carbohydrate fermentation etc. These activities are performed by secretion of enzymes. Hence, this concept is utilized in targeting various drugs to the colon. The enzymatic reactions carried out by the colonic bacteria are acetylation, decarboxylation, dehalogenation, dealkylation of O-alkyl groups and N- alkyl groups, desamination, dehydroxylationesterification, heterocyclic ring fission, hydrolysis, reduction 6,13,17. The activities of these bacteria is affected by various factors including age, colonic diseases, drugs etc.

7.          Strategies for targeting drugs to colon in treatment and prevention of CRC

The systems that are used for CoDDS include pH dependent system, microbial triggered system, pH and microbial triggered double dependent system and bioadhesive system.

7.1.     pH dependent system

This system utilizes the concept of pH in GIT to deliver the drugs in the colon. The drug is either coated or embedded in the polymer matrix. The polymer used in this system has a pH dependent solubility whereby it only gets solubilize at the colonic pH and therefore the intact drug molecule can be easily administered in the colon without its absorption in the upper part of GIT 13. The most commonly used pH dependent polymers for CoDDS are Eudragit S-100 and Eudragit FS 30D (Evonik) that dissolves at pH 7 6. This system can be formulated into tablet, capsule, pellets, beads, microparticles, microsphere, nanoparticles and nanogels 15. The major limitation of this system is lack of specificity and premature drug release due to drastic variability in the GI pH. One of the studies utilizes this approach to prepare nanogels. Copolymer of methyl methacrylate and 2 ethyl hexyl acrylate is used as a pH sensitive polymer to prepare nanogels of 5 FU using solvent evaporation technique. In vitro release study confirms the pH sensitive drug release behaviour of this copolymer which shows highest and sustained release at pH 7.4. Cytotoxicity study was done using HCT-116 cell line whereby it was ascertained that 5 FU loaded nanogels showed higher cytotoxicity as compared to free 5 FU 37.

7.2.     Microbial triggered system

This system utilizes the concept of enzymatic degradation by bacteria residing in the colon. The bacteria present in the colon secrete various enzymes such as, azareducatase, arabinosidase, deaminase, galactosidase, glucoronidase, nitroreductase, pectinase, urea dehydroxylase, xylosidase etc for the fermentation of undigested food from the small intestine 15,20. This system uses biodegradable polymers which protect the drug in the upper part of GIT and gets degraded on reaching the colon resulting in the drug release. Site specific delivery of drug remains the biggest advantage of this system 6,13,20. Two approaches can be designed by using this system i. Prodrug approach and ii. Polysaccharide approach.

7.2.1.     Prodrug approach

Prodrug is the inactive form of the parent drug molecule which upon enzymatic activation results in the conversion of active moiety. In this approach the drug is covalently linked with the biodegradable polymer such that the whole complex is protected from the upper part of the GIT and the drug get release after reaching the colon by bacterial enzyme. Azo conjugates are the most researched one in this category 13,15. Prodrug of 5 Fu was synthesized by conjugating 5 FU with a galactose containing polysaccharide. This prodrug conjugate is intended to release in the colon by colonic enzyme and thus protecting it from the upper part of GIT where the prodrug conjugate is not able to hydrolyse. When this prodrug is given to mice, 5 FU is undetectable in the stomach and intestinal tissue but its majority is detected in distant ileum, cecum, colon and rectum confirming the targeted delivery of 5 FU prodrug to the colon. In vivo studies of 5-FU prodrug reveal an increase in survival rate as well as decrease in tumor weight in the treated mice 38.

7.2.2. Polysaccharide approach

Unlike prodrug where the drug is covalently linked to the carrier, this approach uses drug that can be either coated or embedded in the polysaccharide matrix. An ample of research is going on by using polysaccharide approach mainly due to its biodegradability and inexpensiveness 15. The combination of polysaccharide is gaining more importance than using the single one for targeting drugs specifically to the colon 20. The commonly used polysaccharide includes guar gum, xanthan gum, sodium alginate, pectin, chitosan. Compression coated tablets were prepared using granulated chitosan as a compression coat and 5 FU as a model drug, it is checked for targeted delivery to colon. In vitro release studies revealed that the granulated chitosan protects the formulation from upper part of GIT. Roentgenography study was done in beagle dogs that confirmed the delivery of drug to the colon with protection in upper part of the GIT 39.

7.3.     pH and microbial triggered system

This double dependent system utilizes both the approaches whereby the pH sensitive polymer is coated over a polysaccharide matrix containing the drugs. The role of pH sensitive polymers is to protect the polysaccharide matrix from the upper part of the GIT where it may get solubilize causing premature drug release. The main aim of using double dependent systems was to overcome the limitations associated with both the approaches when used alone. When pH sensitive and polysaccharide approach is used alone it may cause premature drug release due to high variation in pH of GIT and due to solubilisation of polymer in the upper part of GIT respectively. These double dependent systems provide the successful delivery of drug to the colon with least release in the upper part of GIT. Many reports of CoDDS are available using this approach. One of the studies carried out by Ziyaur Rehman et al, 2006 elaborated on preparation of sodium alginate microsphere of 5 FU using emulsion cross linking method 40. This core microsphere containing drug was coated with Eudragit S-100 which dissolved at pH 7. The in vitro release studies of both the uncoated and coated microsphere were carried out. The uncoated microsphere started releasing the drug in the stomach and small intestinal pH but the coated microsphere restricted the drug release in both the pH thereby releasing the drug in pH 7.4 which mimicked the pH of the colon. The in vivo pharmacokinetic studies revealed the detection of drug only in the colonic region which confirmed its targeted delivery to the colon 40, 41. This double dependent approach uses the GI transit time and the pH of GI tract. In this system the polymer is coated to the time dependent matrix containing drugs. The polymer coating provides the protection from stomach pH and the time dependent polymer delay the release until the ileocecal junction 6. A multiunit system consisting of pellets were prepared and a double coat was applied over it using time dependent coat of Eudragit NE30D and pH dependent layer of Eudragit FS30D. Avicel PH101 was used as a spheronization aid and HPMC K4M was used as a binder. The in vitro drug release studies confirmed the release of drug in the colon with 15% w/w of inner and outer coating level 42.

7.4.     Bioadhesive system

Bioadhesion is a process in which a dosage form is adhered to the biomembrane allowing longer residence time thus high local concentration and good absorption. This approach is also used for CoDDS especially for poorly absorbable drug whereby the dosage form remains intact to the colonic mucosa. Many bioadhesive polymers have been investigated which include polycarbophils, polyurethanes and polyethylene oxide, polypropylene oxide copolymers 42. Mucoadhesive microspheres (MAMs) were prepared by Ahmed MZ et al, 2012 using Assam bora rice starch. Double emulsion solvent evaporation technique was used to prepare the microsphere. MAMs were checked for its in vitro and in vivo drug release. The in vitro drug release study assured the insignificant release of drug till 5 h (<8%). The drug release was 94% till 24 h which confirmed its release in the colon. 5 FU was highly detectable (92%) in the colon after 8 h and very insignificant amount of 5 FU was detectable in stomach and small intestine. Mucoadhesion test was done using goat GI mucous membrane which confirms the highest adhesion of 23 h in the phosphate buffer of pH 7.4 43.

8.          CONCLUSION

From a commercial point of view, drug delivery system that is simple and scalable is always preferred. Designing and manufacturing of complicated system is often costly and not proper. A novel drug delivery system like CoDDS exhibits improved bioavailability at site and also circumvents side effects. The technology is robust and dosage form is scalable using standard equipment used in conventional oral dosage forms. Extensive research has been dedicated to target actives to the colon. Of all the systems, the pH dependent system and polysaccharide system is considered to be the most feasible and scalable. Unfortunately, none of the systems described in this review have been developed into a commercial product to treat CRC.

9.          CONTRIBUTORS

       Mudassir Ansari and Kavita Singh: All authors equally contributed in this manuscript for the all tasks.

10.       DECLARATION OF INTERESTS

       We declare no competing interests.

11.       FUNDING: No funding received

12.      REFERENCES

1.       Patel, M. M. Getting into the Colon: Approaches to Target Colorectal Cancer. Expert Opin. Drug Deliv. 2014, 11 (9), 1343–1350. https://doi.org/10.1517/17425247.2014.927440.

2.       Patel, M. M.; Amin, A. F. Formulation and Development of Release Modulated Colon Targeted System of Meloxicam for Potential Application in the Prophylaxis of Colorectal Cancer. Drug Deliv. 2011, 18 (4), 281–293. https://doi.org/10.3109/10717544.2010.538447.

3.       Lin, C.; Ng, H.; Pan, W.; Chen, H.; Zhang, G.; Bian, Z.; Lu, A.; Yang, Z. Exploring Different Strategies for Efficient Delivery of Colorectal Cancer Therapy. Int. J. Mol. Sci. 2015, 16 (11), 26936–26952. https://doi.org/10.3390/ijms161125995.

4.       Colorectal Cancer Prevention and Early Detection What Is Colorectal Cancer ?

5.       Dna, A. Colorectal Cancer What is cancer ? What is colorectal cancer ? http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-cancer-treating-radiation-therapy.

6.       Krishnaiah, Y. S. R.; Khan, M. a. Strategies of Targeting Oral Drug Delivery Systems to the Colon and Their Potential Use for the Treatment of Colorectal Cancer. Pharm. Dev. Technol. 2012, 17 (5), 521–540. https://doi.org/10.3109/10837450.2012.696268.

7.       Kelloff, G. J.; Schilsky, R. L.; Alberts, D. S.; Day, R. W.; Guyton, K. Z.; Pearce, H. L.; Peck, J. C.; Phillips, R.; Sigman, C. C. Colorectal Adenomas : A Prototype for the Use of Surrogate End Points in the Development of Cancer Prevention Drugs Colorectal Adenomas : A Prototype for the Use of Surrogate End Points in the Development of Cancer Prevention Drugs. Clin. Cancer Res. 2004, 10 (301), 3908–3918. https://doi.org/10.1158/1078-0432.CCR-03-0789.

8.       Stewart, S. L.; Wike, J. M.; Kato, I.; Lewis, D. R.; Michaud, F. A Population-Based Study of Colorectal Cancer Histology in the United States, 1998-2001. Cancer 2006, 107 (1), 1128–1141. https://doi.org/10.1002/cncr.22010.

9.       Levine, J. S.; Ahnen, D. J. Adenomatous Polyps of the Colon — NEJM. N. Engl. J. Med. 2012, 6 (8), 2551–2557.

10.    Bond, J. H. Polyp Guideline: Diagnosis, Treatment, and Surveillance for Patients with Nonfamilial Colorectal Polyps. The Practice Parameters Committee of the American College of Gastroenterology. Ann. Intern. Med. 1993, 119 (11), 836–843. https://doi.org/10.1111/j.1572-0241.2000.03434.x.

11.    Jacobson, J. S.; Neugut, A. I. Interpreting Preeursor Studies: What Polyp Trials Tell Us about Large-Bowel Cancer. J. Natl. Cancer Inst. 1994, 86 (21), 1648. https://doi.org/10.1093/jnci/86.21.1648.

12.    Nasrallah, A.; Saykali, B.; Al Dimassi, S.; Khoury, N.; Hanna, S.; El-Sibai, M. Effect of StarD13 on Colorectal Cancer Proliferation, Motility and Invasion. Oncol. Rep. 2014, 31 (1), 505–515. https://doi.org/10.3892/or.2013.2861.

13.    Patel, A.; Bhatt, N.; Patel, K. R.; Patel, N. M.; Patel, M. R. Colon Targeted Drug Delivery System : A Review System. J. Pharm. Sci. Biosci. Res. 2011, 1 (1), 37–49.

14.    Challa, T.; Vynala, V.; Allam, K. V. Colon Specific Drug Delivery Systems: A Review on Primary and Novel Approaches. Int. J. Pharm. Sci. Rev. Res. 2011, 7 (2), 171–181.

15.    Rajguru, V. V.; Gaikwad, P. D.; Bankar, V. H.; Pawar, S. P. An Overview on Colonic Drug Delivery System. Int. J. Pharm. Sci. Rev. Res. 2011, 6 (2), 197–204.

16.    Gupta, V. K.; Gnanarajan, G.; Kothiyal, P. THE PHARMA INNOVATION A Review Article on Colonic Targeted Drug Delivery System INTRODUCTION : Phama Innov. 2012, 1 (7), 14–24.

17.    Tiwari, G.; Tiwari, R.; Wal, P.; Wal, A.; Rai, A. K. Primary and Novel Approaches for Colon Targeted Drug Delivery – A Review. Int. J. Drug Deliv. 2010, 2 (6), 1–11. https://doi.org/10.5138/ijdd.2010.0975.0215.02006.

18.    Kolte, B. P.; Tele, K. V.; Mundhe, V. S.; Lahoti, S. S. Colon Targeted Drug Delivery System – A Novel Perspective. Asian J. Biomed. Pharm. Sci. 2012, 2 (4), 21–28. https://doi.org/10.15272/AJBPS.V2I14.131.

19.    Philip, A. K.; Philip, B. Colon Targeted Drug Delivery Systems: A Review on Primary and Novel Approaches. Oman Med J 2010, 25 (2), 79–87. https://doi.org/10.5001/omj.2010.24\nOMJ-D-10-00028 [pii].

20.    Amidon, S.; Brown, J. E.; Dave, V. S. Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches. AAPS PharmSciTech 2015, 16 (4), 731–741. https://doi.org/10.1208/s12249-015-0350-9.

21.    Markowitz, S. D.; Dawson, D. M.; Willis, J.; Willson, J. K. V. Focus on Colon Cancer. Cancer Cell 2002, 1 (3), 233–236. https://doi.org/10.1016/S1535-6108(02)00053-3.

22.    Information, G.; Colon, A. Colon Cancer Treatment ( PDQ ฎ ) Patient Version Table of Contents.

23.    Markowitz, S.; Bertagnolli, M. Molecular Basis of Colorectal Cancer. N. Engl. J. Med. 2009, 361 (25), 2449–2460. https://doi.org/10.1056/NEJMra0804588.Molecular.

24.    Bevacizumab, A. Drugs Approved for Colon and Rectal Cancer Drugs Approved for Colon Cancer Drug Combinations Used in Colon Cancer Drugs Approved for Rectal Cancer Drugs Approved for Gastroenteropancreatic Neuroendocrine Tumors.

25.    Umar,  a; Viner, J. L.; Hawk, E. T. The Future of Colon Cancer Prevention. Ann. N. Y. Acad. Sci. 2001, 952 (5), 88–108.

26.    Das, D.; Arber, N.; Jankowski, J. A. Chemoprevention of Colorectal Cancer. Digestion 2007, 76 (1), 51–67. https://doi.org/10.1159/000108394.

27.    Sporn, M. B. Approaches to Prevention of Epithelial Cancer during the Preneoplastic Period. Cancer Res. 1976, 36 (7 II), 2699–2702.

28.    Shukla, Y.; Pal, S. K. Dietary Cancer Chemoprevention : An Overview. Int. J. Hum. Genet. 2004, 4 (4), 265–276.

29.    Kurt Kroenke, Dale Theobald, Jingwei Wu, Julie K. Loza, Janet S. Carpenter,  and W. T. The Association of Depression and Pain with Health-Related Quality of Life, Disability, and Health Care Use in Cancer Patients. J. Pain Symptom Manage. 2010, 40 (3), 327–341. https://doi.org/10.1097/MPG.0b013e3181a15ae8.Screening.

30.    Harun, Z.; Ghazali, A. R. Potential Chemoprevention Activity of Pterostilbene by Enhancing the Detoxifying Enzymes in the HT-29 Cell Line. Asian Pacific J. Cancer Prev. 2012, 13 (12), 6403–6407. https://doi.org/10.7314/APJCP.2012.13.12.6403.

31.    Pasi J, A and Robert M, J. Chemoprevention of Colon Cancer. N. Engl. J. Med. 2000, 342 (26), 1960–1968.

32.    Karin Gwyn, F. A. S. Chemoprevention of Colorectal Cancer. Am. J. Gastroenterol. 2002, 97 (1), 13–21.

33.    Teixeira, M. C.; Braghiroli, M. I.; Sabbaga, J.; Hoff, P. M. Primary Prevention of Colorectal Cancer: Myth or Reality? World J. Gastroenterol. 2014, 20 (41), 15060–15069. https://doi.org/10.3748/wjg.v20.i41.15060.

34.    Stelmaszuk T, Jałocha L, Wojtuń S, G. J. Chemoprewencja Raka Jelita Grubego [Chemoprevention of Colorectal Cancer]. Pol Merkur Lek. 2009, 26 (155), 565–568.

35.    Ali Asgar, L. F.; Chandran, S. Multiparticulate Formulation Approach to Colon Specific Drug Delivery: Current Perspectives. J. Pharm. Pharm. Sci. 2006, 9 (3), 327–338. https://doi.org/10.1016/j.jconrel.2008.11.011.

36.    Gandhi, B.; Baheti, J. Multiparticulates Drug Delivery Systems : A Review. Int. J. Pharm. Chem. Sci. 2013, 2 (3), 1620–1626.

37.    Ashwanikumar, N.; Kumar, N. A.; Asha Nair, S.; Vinod Kumar, G. S. Methacrylic-Based Nanogels for the PH-Sensitive Delivery of 5-Fluorouracil in the Colon. Int. J. Nanomedicine 2012, 7 (9), 5769–5779. https://doi.org/10.2147/IJN.S31201.

38.    Lengsfeld, C. S.; Shoureshi, R. A. (19) United States (12), 2008.

39.    Yassin, A. E. B.; Alsarra, I. a; Alanazi, F. K.; Al-Mohizea, A. M.; Al-Robayan, A. a; Al-Obeed, O. a. New Targeted-Colon Delivery System: In Vitro and in Vivo Evaluation Using X-Ray Imaging. J. Drug Target. 2010, 18 (1), 59–66. https://doi.org/10.3109/10611860903165022.

40.    Rahman, Z.; Kohli, K.; Khar, R. K.; Ali, M.; Charoo, N. a; Shamsher, A. a a. Characterization of 5-Fluorouracil Microspheres for Colonic Delivery. AAPS PharmSciTech 2006, 7 (2), E1-9. https://doi.org/10.1208/pt070247.

41.    Rahman, Z.; Kohli, K.; Zhang, S.-Q.; Khar, R. K.; Ali, M.; Charoo, N. a; Tauseef, M.; Shamsher, A. a a; Mohammed, N. N.; Repka, M. a. In-Vivo Evaluation in Rats of Colon-Specific Microspheres Containing 5-Fluorouracil. J. Pharm. Pharmacol. 2008, 60 (5), 615–623. https://doi.org/10.1211/jpp.60.5.0007.

42.    Kulthe, S. S.; Bahekar, J. K.; Godhani, C. C.; Choudhari, Y. M.; Inamdar, N. N.; Mourya, V. K. Modulated Release of 5-Fluorouracil from PH-Sensitive and Colon Targeted Pellets: An Industrially Feasible Approach. Drug Dev. Ind. Pharm. 2013, 39 (1), 138–145. https://doi.org/10.3109/03639045.2012.660951.

43.    Ahmad, M. Z.; Akhter, S.; Anwar, M.; Ahmad, F. J. Assam Bora Rice Starch Based Biocompatible Mucoadhesive Microsphere for Targeted Delivery of 5-Fluorouracil in Colorectal Cancer. Mol. Pharm. 2012, 9 (11), 2986–2994. https://doi.org/10.1021/mp300289y.