The JournalofPharmaceutical Sciences and Medicinal Research

Vol. 001, Issue 03, Pg. No.: 045 – 060 Review Article

TheJournalofPharmaceuticalSciencesandMedicinalResearch

© 2021 The Journal of Pharmaceutical Sciences and Medicinal Research Page | 45

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: [email protected]

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

The Journal of Pharmaceutical Sciences and Medicinal Research Ansari et al

The J. Pharm. Sci. and Med. Res. (001) (03) (045-060) Page | 46

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

Abbreviations:

COX, Cyclo-oxygenase; PPAR-Y, Peroxisome proliferator-activated receptor gamma; CDK, Cyclin

dependent kinase; MMP, Matrix metalloproteinase; iNOS, Induce nitric oxide synthase.

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.



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

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