review on-colon targated drug delivery system. rpa1516254015.pdfdrug delivery to the colon is...

47 | P a g e International Standard Serial Number (ISSN): 2319-8141

Full Text Available On www.ijupbs.com

International Journal of Universal Pharmacy and Bio Sciences 4(6): November-December 2015

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.093***

ICV 5.13***

Pharmaceutical Sciences REVIEW ARTICLE …………!!!

REVIEW ON-COLON TARGATED DRUG DELIVERY SYSTEM

Shinde V.S. 1*

, Shinkar D.M. 2, Saudagar R.B.

3

Department Of Pharmaceutics, R. G. Sapkal College of pharmacy, Anjaneri, Nashik.

KEYWORDS:

Need, Factors affecting

CDDS, Approaches of

CDDS, Evaluation.

For Correspondence:

Shinde V.S. *

Address:

Department Of

Pharmaceutics, R. G.

Sapkal College of

pharmacy, Anjaneri,

Nashik.

ABSTRACT

The colon drug delivery has a number of important implications in the

field of pharmacotherapy. It has been exploited for local as well as

systemic delivery of active drugs. Various diseases including

Inflammatory Bowel Diseases (IBD) can be effectively treated by the local

delivery of drugs to the large intestine. The treatment of large intestine

disorders, such as Crohn's disease, irritable bowel syndrome, colitis, colon

cancer and local infectious disease. The specific release in the colon also

affects a time delay between administration and onset of action, which can

useful for diseases with various degrees of severity, such as asthma and

arthritis.



INTRODUCTION:

Targeted drug delivery to the colon is highly desirable for local treatment of a variety of

bowel disease such as ulcerative colitis, crohn's disease, amebiosis, colonic cancer and for

local treatment of local colonic pathologies, and the systemic delivery of protein and peptide

drugs1,2

. Dosage forms that deliver drug in the colon rather than upper GIT has number of

advantages. Oral delivery of drugs in the colon is valuable in the treatment of diseases of

colon where by high local concentration can be achieved while minimizing side effects. The

colon is attracting interest as a site where poorly absorbed drug molecule may have an

improved bioavailability because the colon has long retention time and appears highly

responsible to agents that enhance the absorption of poorly absorbed drugs. The simplest

method for targeting of drugs to the colon is to obtain slower release rates or longer release

periods by the application of thicker layers of conventional enteric coating or extremely slow

releasing matrices. There are various method or techniques through which colon drug

targeting can be achieved, for example, formation of prodrug, coating with pH sensitive

polymers, coating with biodegradable polymers, designing formulation using polysaccharide,

timed released systems, pressure-controlled drug delivery systems, osmotic pressure

controlled systems. Coating of the drugs with pH sensitive polymers provides simple

approach for colon specific drug delivery. Drug delivery to the colon is beneficial not only

for the oral delivery of proteins and peptide drugs (degraded by the digestive enzymes of

stomach and small intestine) but also for the delivery of low molecular weight compounds

used to treat diseases associated with the colon or large intestine.

Need of colon targeted drug delivery:3

Targeted drug delivery to the colon would ensure direct treatment at the disease site,

lower dosing and fewer side effect.

Site-specific or targeted drug delivery system would allow oral administration of

peptide and protein drugs, colon specific formulation could also be used to prolong

the drug delivery.

The colon is a site where both local or systemic drug delivery could be achieved,

topical treatment of inflammatory bowel diseases, e.g. ulcerative colitis or Crohn's

disease .Such inflammatory conditions are usually treated with glucocorticoids and

sulfasalazine (targeted).

A number of others serious diseases of the colon, e.g. colorectal cancer, might also be

capable of being treated more effectively if drugs were targeted to the colon.



Formulations for colonic delivery are also suitable for delivery of drugs which are

polar and/or susceptible to chemical and enzymatic degradation in the upper GI tract,

highly affected by hepatic metabolism, in particular, therapeutic proteins and

peptides.

Advantages over conventional Drug Delivery:18

Ulcerative colitis and cirrhosis disease are currently treated with glucocorticoids,

and other anti-inflammatory agents.

Utilization of drug is more.

Side effects can be reduced.38

Lesser amount of doses required comparatively.39

Limitations:29

Multiple manufacturing steps.

Incomplete release of drug.

Lowering of bioavailability due to binding of drugs to intestinal contents.

Several factors like properties of drug, delivery system, interaction with GIT contents play a

major role in the successful delivery of drug. The luminal fluid in the colon plays a major

role in the absorption of the drugs. The luminal fluid in the colon is less compared to the

small intestine. The drug should be in soluble state for the successful absorption. To prevent

the decreased availability of low soluble drugs the drug should be delivered in presolubilized

form. The key factors to be considerd while targeting the drug to the specific organ like colon

are pH of GIT, drug solubility ,contents of GIT, microbial flora, transit time of the intestine,

etc.

Table-1 Colonic diseases, its site and active drug components4

Targated site Diseases Drug

Local Colorectal cancer, Cystic fibrosis,

Chronic pancreatitis, Pancreatactomy.

5-fluorouracil, Digestive

enzyme.

Systemic Oral delivery of vaccines, To prevent

gastric irritation, To prevent first pass

metabolism of orally administered drugs,

Oral delivery of peptides.

Typhoid, Steroids,

NSAIDS, Insulin.

Topical Inflammatory bowel diseases(Crohn's

diseases, Ulcerative colitis), Irritable

bowel diseases, Amoebiasis.

Hydrocortisone, Prednisolone,

Sulfasalazine, Mesalazine,

Mercaptopurine, Tinidazol,

Mebendazole.



Anatomy of Colon:37

Fig-1 Anatomy of Colon

The GIT measures about 5 meters long. The different parts of GIT are divided into upper and

lower gastrointestinal tract. The upper GIT includes oesophagus, stomach, and duodenum.

The lower GIT includes small intestine and large intestine. The small intestine measures an

average of about 6.9 meters to 7.1 meters. It include duodenum, jejunum and ileum. The main

function of small intestine is the absorption of nutrients and mineral from food. The retension

time of small intestine is 3-5 hr. The large intestine extending from the ileocaecal junction to

the anus is divided into three main parts i.e. colon, the rectum and anal canal. The entire

colon is about 5 feet (150 cm) long, and is divided in to five major segments. Peritoneal folds

called as mesentery which is supported by ascending and descending colon. The right colon

consist of the caecum, ascending colon, hepatic flexure and the right half of the transverse

colon. The left colon contain the left half of the transverse colon, descending colon, splenic

flexure and sigmoid. The rectum is the last anatomic. The colon is having high water

absorption capacity, the colonic contents are considerably viscous and their mixing is not

efficient, thus availability of most drugs to the absorptive membrane is low. The human colon

has over 400 distinct species of bacteria as resident flora, a possible population of up to 1010

bacteria per gram of colonic contents. The major function of colon is the creation of suitable



environment for the growth of colonic microorganisms, storage reservoir of faecal contents,

expulsion of the contents of the colon at an appropriate time and absorption of potassium and

water from the lumen. The absorptive which more than 90% of the fluid is absorbed. Among

the reactions carried out by these gut flora capacity is very high, each about 2000ml of fluid

enters the colon through the ileocaecal valve are azoreduction and enzymatic cleavage i.e.

glycosides. These metabolic processes may be responsible for the metabolism of many drugs

and may also be applied to colon targeted delivery of peptide based macromolecules such as

insulin by oral administration.

Table-2 Measures of different parts of GIT29

Organ Length

Small intestine:

Duodenum

Jejunum

Ileum

3m

25cm

1m

2m

Large intestine:

Caecum Colon

Ascending colon

Transverse colon

Descending colon

Sigmoid portion

1.5m

6cm

20-25cm

10-15cm

40-45cm

35-40cm

Rectum 20cm

Anal canal 3cm

Factors affecting colon targeted delivery:

1.Physiological factors

2.Pharmaceutical factors

1. Physiological factors

a. Gastric emptying time29

Gastric emptying is test that measures the time it takes for food to empty from the stomach

and enter the small intestine. Drug delivery to the colon upon oral administration depends

mainly on gastric emptying and bowel transit time. Upon reaching the colon the transit time

of dosage form depends on the size of the particles. Smaller particles have more transit time



compared to larger particles. Diarrhoea patients have shorter transit time where as

constipation patients have longer gastric transit time.

Table-3 Transit time of different parts of colon5

Part of GIT Transit time

Fasted state

Fed state

Small intestine transit

Colon transit

10min – 2hr

>2hr

3-4hr

20-35hr

b. pH of colon:29

The pH of GIT varies between different individuals. The food intake, diseased state, etc.

influences the pH of the GIT. This change in the pH in different parts of GIT is the basis for

the development of colon targeted drug delivery systems. Coating with different polymers is

done to target the drug to the site.

Table-4 pH in different parts of colon

Part of GIT pH

Stomach Fasted state 1.5-2

Fed state 2-6

Small intestine 6.6- 7.5

Colon:

Ascending colon

Transverse colon

Descending colon

6.4

6.6

7.0

c. Colonic microflora and Enzymes29

The GIT contains a variety of microorganism that produces many enzymes need for

metabolism. Growth of this microflora is controlled by the GIT contents and peristaltic

movements. The enzymes released by different microorganism like E.coli ,Clostridia,

Lactobacilli, Eubacteria, Streptococci are responsible for the various metabolic reactions that

takes place in the GIT.



Table-5 Different microflora, enzymes released and action

Microorganism Enzyme Metabolic reaction

E.coli, Bacteroids Nitroreductase Reduces aromatic and

heterocyclic nitro compound

Clostridia, Lactobacilli Hydrogenase Reduces carbonyl groups &

aliphatic double bonds

Clostridia, Eubacteria Glucosedase Cleavage of b-glycosidase of

alcohols and phenols

Eubacteria,Clostridia,

Streptococci

sulfasetase Cleavage of o-sulphates and

sulfamates

2. Pharmaceutical Factor

a. Drug Candidate6

Drugs which shows poor absorption from stomach as intestne including peptide are most

suitable for CDDS. The drug used in treatment of IBD, ulcerative colitis, diarrhoes and colon

cancers are ideal candidates for local colon delivery.

Table-6 Criteria for selection of drugs for CDDS7

Criteria Pharmacological

class

Non peptide drug Peptide drug

Drugs used for local

action in colon

against GIT diseases

Anti-inflammatory

drugs

Metoprolol,

Nifedipine

Amylin,

Oligonucleotide

Drugs used for colon

cancer

Ant-ineoplastic drugs Pseudoephedrine Epoetin, Glucagon

Drugs poorly

absorbed

Anti-hypertensive

and Anti-anginal drugs

Ibuprofen,

Theophylline

Cyclosporine,

Desmopressin

Drugs that undergo

extensive first pass

metabolism

Nitroglycerin and

Corticosteroids

Bleomycin, Nicotine Sermorelin,

Saloatonin



b.Drug Carrier8

The selection of carrier for particular drug candidate depends on the physicochemical nature

of the drugs as well as the disease for which the system is to be used. The factor such as

chemical nature, stability and partition coefficient of drug and the type of absorption

enhancers chosen influence the carrier selection. Moreover, the choice of drug carrier

depends on the functional groups of drug molecule, etc.

Approaches for colon targeted drug delivery:33

In general, seven primary approaches have been proposed for targeted colon delivery,

namely,

1.Transit time dependent colonic DDS

2.pH dependent colonic DDS

3.pH and time dependent colonic DDS

4.Bacterial enzyme dependent colonic DDS

Prodrug based systems

a. Azo prodrug

b. Polymerric /Saccharide prodrug

c. Amino acid prodrug

5.pH and bacterial enzyme dependent colonic DDS

6.Colonic pressure controlled DDS

7.Osmotic pressure controlled colonic DDS.

1. Transit time dependent colonic DDS:34

The basic principle involved in the system is that the release of drug from dosage form should

be after a predetermined lag time to deliver the drug at the right site of action at right time

and in the right amount. It is also known as pulsatile release, delayed or sigmoidal release

system. This approach is based on the principle of delaying the release of the drug until it

enters into the colon.

The disadvantages of this systems are:

a. Gasrtic emptying time varies markedly between subject or in a manner dependent on type

and amount of food intake.

b. Gastrointestinal movement, especially peristalsis or contraction in the stomach would

result in change in Gastrointestinal transit of the drug.

c. Accelerated transit through different regions of the colon has been observed in patients

with the IBD, the carcinoid syndrome and diarrhoea and the ulcerative colitis. Combination



of hydrophilic (HPMC) and hydrophobic polymers has been used as coating for tablets that

release the drug from a core after a lag time.20,28

2. pH dependent colonic DDS:9

In the stomach, pH ranges between 1 and 2 during fasting but increases after eating. The pH

is about 6.5 in the proximal small intestine and about 7.5 in the distal small intestine.From the

ileum to the colon, pH declines significantly. It is about 6.4 in the cecum. However, pH

values as low as 5.7 have been measured in the ascending colon in healthy volunteers. The

pH in the transverse colon is 6.6 and 7.0 in the descending colon. Use of pH dependent

polymers is based on these differences in pH levels. The polymers described as pH dependent

in colon specific drug delivery are insoluble at low pH levels but become increasingly soluble

as pH rises.Although a pH dependent polymer can protect a formulation in the stomach and

proximal small intestine, it may start to dissolve in the lower small intestine and the site-

specificity of formulations can be poor.

Table-7 Different polymer and their pH value18

Polymer Threshold pH

Eudragit L100 6.0

Eudragit S100 7.0

Eudragit L-30D 5.6

Eudragit FS-30D 6.8

HPMC pthalate 50 5.2

HPMC pthalate 55 5.4

Cellulose acetate

Trimellate

4.8

Fig 2: Drug release pattern of a multilayer coated system at different pH conditions in

GIT



3. pH and time dependent colonic DDS:33

The transit time through the small intestine is independent of the formulation. But, the time

taken by the formulation to leave the stomach varies greatly. Hence, the time of arrival of a

formulation in the colon cannot be accurately predicted. However, the effects of variation in

gastric residence time can be minimized by using systems that prevents drug release until 3-4

hr after leaving the stomach. A multiple coated oral dosage form consisting of core coated

with three polymeric layers has developed. A novel oral time based drug release system for

colon specific delivery. The system designed to exploit the relatively constant small intestinal

transit time of dosage forms consist of drug containing cores coated with three polymeric

layers. The outer layer dissolved at pH >5, then the intermediate swellable layer, made of an

enteric material. The system provides the expected delayed release pattern, as also indicated

by the preliminary in vivo studies on rats. Several other drug delivery systems have

developed that rely upon the relatively constant transit time of small intestine. A novel

delivery system was developed for delivering drugs to the colon by selecting

polymethacrylates with appropriate pH dissolution characteristic for the distal end of the

small intestine.

4. Bacterial enzyme dependent colonic DDS:14,15,16,17

The microflora of the colon is in the range of 1011

-1012

Cfu/ml consisting mainly of anaerobic

bacteria, e.g. Bacteroides Bifid bacterium, Eubacteria, Clostridia, Enterococci, and

Ruminococcus etc. These microflora fulfills its energy needs by fermenting various types of

substrates that been left undigested in the small intestine, like di and trisaccharides,

polysaccharides etc. For this fermentation, the micro flora produces a vast number of

enzymes like glucoronidase, xylosidase, arabinosidase, galactosidase, nitroreductase,

azareductase, deaminase, and urea dehydroxylase. Because of the presence of the

biodegradable enzymes only in the colon, the use of biodegradable polymers for colon-

specific drug delivery seems to be a more site-specific approach as compared to other

approaches. These polymer shield the drug from the enviornment of stomach and small

intestine, and are able to deliver the drug to the colon. On reaching the colon, they undergo

assimilation by micro-organism, or degradation by enzyme or break down of the polymer

back bone leading to a subsequent reduction in their molecular weight and thereby loss of

mechanical strength. They are then anable to hold the drug entity any longer. The majority of

bacteria are present in the colon they are distributed throughout the GI tract. Endogenous and

exogenous substrates, such as carbohydrate and proteins, escape digestion in the upper GI



tract but are metabolized by the enzyme sercreted by colonic bacteria. Sulfasalazine, a

prodrug consist of the active ingredient of mesalazine, was the first bacteria sensitive delivery

system designed to deliver the drug to the colon. Use of polysaccharides offers an alternative

substrate for the bacterial enzymes present in the colon. Most of the polymers are used in

pharmaceutical composition and are considerd generally regarded as safe (GRAS) recipients.

The enzymes present in the colon are:30

A.Reducing enzymes: Nitroreductase, Azoreductase, N-oxide reductase, Sulfoxide reductase,

Hydrogenase etc.

B.Hydrolytic enzymes: Esterase, Amidase, Glycosidase, Glucuronidase, Sulfatase etc.

Prodrug based system:37

Fig-3 Prodrug System

Classical prodrugs design often represents a non-specific chemical approach to mask

unwanted drug properties such as low bioavailability, less site specific, and chemical

instability. On the other hand, targeted prodrug design represents a new strategy for directed

and efficient drug delivery. Particularly, prodrugs targeting to the specific enzymes or a

specific membrane transporter, or both, have potential drug delivery system especially for

cancer chemotherapy. Prodrug is the main approach of microbial triggered drug delivery

system in which the drug release from the formulation is triggered by the microflora present

in the gut. Prodrug is inactive form of an active parent drug that undergoes enzymatic

transformation to releasethe active drug. The prodrug are prepared by the linking the active

drug with hydrophobic moietis like amino acid, glucoronic acids, glucose, galactose,

cellulose, etc. These prodrug molecules get hydrolysed in the presence of the enzymes



released by the micro flora or specific membrane transporter, or both, have potential drug

delivery system especially for the cancer chemotherapy.

a. Azo prodrug:

In this type of conjugation drug is conjugated with an azo bond to the carrier. These azo

compounds are extensively metabolized by the intestinal bacteria, both by intracellular

enzymatic component and extracellular reduction. This azo bond is stable in the upper GIT

and is cleaved in the colon by the azo reductases produced by the micro flora. Ex.

Sulfasalazine is introduced for the treatment of rheumatoid arthritis and anti-inflammatory

disease. Chemically it is salicylazosulphapyridine (SASP), where sulphapyridine is linked to

a salicylate radical by an azo bond. When taken orally, only a small proportion of the

ingested dose is absorbed from the small intestine and the bulk of the sulfasalazine reaches

the colon intact. After reaching the colon there is split at the azo bond by the colonic bacteria

with the liberation of sulphapyridine and 5-ASA. Some new approaches for the treatment of

IBD have emerged due to the side effects of sulfasalazine. This is done by aminohippurate (4

amino benzoyl glycine), 4-amino benzoyl β-alanine in balsalazine, p-aminobenzoate in HB-

313 or a non-absorbable sulphanilamide ethylene polymer in poly-ASA. The most important

prodrug is osalazine (OSZ) which is dimer having two molecule of 5-ASA that are linked via

an azo bond.18,19,20



b. Polymeric/Saccharide prodrugs:36

The rationale for the development of a polysaccharides based colon delivery system is the

presence of large amount of polysaccharidases in the human colon as it is inhibited by a large

number and variety of bacteria which secrete many enzymes e.g. β- D -glucosidase, β- D -

galactosidase, amylase, pectinase, xylanase, β- D -xylosidase, dextranase etc.10,13

The

bacterial enzymes of colon degrades the carrier polymer and release the content for localized

and systemic absorption through colon.11,12

The list of microbially degradable materials is

given in bellow:

Table-8 Microbially degradable mataerial

Class Example

Disaccharide Lactose, Maltose

Oligosaccharide Cellobiose, Cyclodextrin, Lactulose

Polysaccharide36

Alginates, Amylose, Arabinogalactan, Cellulose,

Chitosan, Dextran, Galactomannan, Inulin, Karaya gum,

Pectin, Starch, Xylan, Xanthan and Tragacanth gum.

C. Amino acid prodrugs:

When free steroids were administered orally, they were almost absorbed in the small intestine

and less than 1% of the oral dose reached the colon. The conjugation of drug molecule to the

polar amino acids and prepared prodrugs for colon drug delivery. Proteins and their basic

units, i.e. amino acids, have polar groups like -NH2 and -COOH. These polar groups are

hydrophilic and reduce the membrane permiability of amino acids and proteins. Various non

essential amino acids such as glycine, tyrosine, methionine, and glutamic acid were

conjugated to salicylic acid. The conjugate showed minimal absorption and degradation in

the upper GI tract and showed more enzymatic specificity for hydrolysis by colonic enzymes.

Glucuronide and sulphate conjugation is the major mechanism for the inactivation and

preparataion for clearance of many drugs. Bacteria of the lower GI tract, however, secrete β-

glucuronidase and can deglucuronidate a variety of drugs in the intestine.

5. pH and bacterial enzyme dependent colonic DDS:

It is also called as CODE(combination of pH dependent and microbial triggered)

This method is developed to minimize the problems associated the pH and time dependent

drug delivery systems. In this systems the pH sensitive polymers are used along with the

polysaccharides that are degraded only by specific bacteria present in the intestine. This



system consists of a core tablet coated with three layers of polymer coatings.21

The outer

coating is composed of the polymer Eudragit L. This coating gets dissolved once the tablet

passes through the pyloric and duodenum and exposes the next coating. The next coating is

composed of Eudragit E. This layer allows the release of lactulose present in the inner core.

This release lactulose gets metabolized into short chain fatty acids that lower the surrounding

pH where the Eudragit E layer dissolves. The dissolving of Eudragit E results in the exposure

of the drug. The other polysaccharides that are used along with the drug in the core tablet are

mannitol, maltose, etc. The bacteria present in the colon are responsible for the degradation

of polysaccharides that are released from the core tablet. The

degradation of polysaccharides results in organic acids formation that lowers the pH of the

contents surrounding the tablet.

Fig-4 pH and bacterial enzyme dependent colonic DDS

6. Colonic pressure controlled DDS:

As a result of peristalsis, higher pressures are encountered in the colon than in the small

intestine. Developed pressure controlled colon-delivery capsules prepared using

ethylcellulose, which is insoluble in water.22

In such systems, drug release occurs following

the disintegration of a water-insoluble polymer capsule because of pressure in the lumen of

the colon. The thickness of the ethylcellulose membrane is the most important factor for the

disintegration of the formulation.23,24

The system also appeared to depend on capsule size and

density. Because of reabsorption of water from the colon, the viscosity of luminal content is

higher in the colon than in the small intestine. IT has therefore been concluded that drug

dissolution in the colon could present a problem in relation to colon-specific oral drug



delivery system. In pressure controlled ethylcellulose single unit capsules the drug is in a

liquid25

. Lag time of three to five hours in relation to drug absorption were noted when

preesure-controled were administered to humans.

7.Osmotic pressure controlled colonic DDS:

This system consists of osmotic units. The osmotic units are used either singly or as many as

pull units that are encapsulated in a hard gelatine capsule. The push pull units are bilayered

with outer enteric impermeable membrane and inner semi permeable membrane. The internal

or central part of the push pull consists of the drug layer and push payer. The semipermeable

membrane which is present next to the drug layer consists of an orifice through which the

drug are expelled during the course of time. The capsule body enclosing the push pull units

gets dissolved immediately after administration. During the passage of the push pull units

through the GIT the enteric impermeable membrane prevents the water absorption into the

unit. The coating gets dissolved once it reaches the small intestine due to higher pH(>7).

Water enters the unit through the semi permeable membrane causing the push layer to swell.

The swelling of the push compartment forces the drug into the surrounding environment

through the orifice. These osmotic controlled drug delivery system deliver the drug at a

constant rate for upto 24hr.

Fig-5 Osmotically controlled CDDS



Evaluation:

a. In vitro evaluation:

No standardized evaluation technique is available for evaluation of CDDS because an ideal in

vitro model should posseses the in vivo conditions of GIT such as pH, volume, stirring,

bacteria, enzymes, enzyme activity and other components of food. Generally these conditions

are influenced by the diet and physical stress and these factors make it difficult to design a

standard in vitro model. In vitro model used for CDDS are:

In vitro dissolution test:

Dissolution of controlled-release formulations used for colon-specific drug delivery are

usually complex, and the dissolution methods described in the USP can not wholly mimic in

vivo conditions such as those relating to pH, bacterial environment and mixing forces.26

Dissolution tests relating to CDDS may be carried out using the conventional basket method.

Parallel dissolution studies in different buffers may be undertaken to characterize the

behaviour of formulations at different pH levels. Dissolution tests of a colon-specific

formulation in various media simulating pH conditions and times likely to be encountered at

various locations in the GIT.27

The media chosen were, e.g. pH 1.2 to simulate gastric fluid,

pH 6.8 to simulate the jejunal region of the small intestine, and pH 7.2 to simulate the ileal

segment. Enteric-coated capsules for CDDS have been investigated in a gradient dissolution

study in three buffers. In vitro test for intactness of coatings and carriers in simulated

conditions of stomach and intestine. Drug released study in 0.1 N HCL for 2 hrs. (mean

gastric emptying time) Drug released study in phosphate buffer for 3 hrs (mean small

intestine transit time).

Preparation of 4% w/v rat caecal content:

Albino rats weighing 150-200 gm were kept on a normal diet and administered 1 ml of 1%

w/v solution of the selected polysaccharide in water. This treatment was continued for 7 days

in induce the specific enzymes responsible for degradation of polysaccharide in vivo. 30 min

before the drug release studies began the anesthetized rats were sacrificed, the rat abdomen

was opened ligatures were made before and after caecum and the caecum was removed under

anaerobic conditions. The caecum bag was opened and its contents were weighed and

homogenized then suspended in phosphate buffer saline (pH 7.4) to give the 4%

concentration of ceacal content. The suspension was centrifuged at 2000 rpm for 10 min at

4˚C to disrupt the bacterial cells followed by sonication. The resultant mixture was



centrifuged at 2000 rpm for 20 min. Because the caecum environment is naturally anaerobic,

all the operations were performed in a CO2 atmosphere.

In vitro release study in rat caecal medium:

The drug release studies were performed in slightly modified dissolution apparatus which

consist of a 250 ml beaker containing 200 ml of rat ceacal content medium was suspended

using iron string into the original jars containing water at 37±0.1ºC. The tablets were placed

in the 200ml dissolution medium containing 4% w/v rat caecal contents. The studies were

performed for 12-24 hrs. Samples were diluted appropriately with phosphate buffer saline

(pH 7.4) and centrifuged at 2000rpm for 10 min. The supernatant was filtered through

whatman filter paper, and the filterate was analysed for drug content using UV

spectrophotometer at 210nm. All experiment was performed in triplicate.

In vitro enzymatic test:18

1. Incubate carrier drug system in fermenter containing suitable medium for bacteria

(Streptococcus faccium or B. Ovatus) amount of drug released at different time intervals

determined.

2. Drug released study is done in buffer medium containing enzymes (enzyme pectinase,

dextranase), or rat or guinea pig or rabbit cecal.

b.In vivo evaluation

The in vivo evaluation of the CDDS is done in dogs, guinea pigs, rats and pigs as they

resemble the anatomic and physiological conditions, microflora of human GIT. The

distribution of various enzymes in GIT of rat and rabbit is comparable to that in human.

Marketed preparation to treat ulcerative colitis and crohn's disease

Drugs Trade Name Dose

Sulfasalazine Azulfidine 2-4 gm/day

Osalazine Dipentum 1 gm/day

Mesalazine Pentaza

Asacol

1.5-4 gm/day

Budenoside Entocost 9 mg/day

CONCLUSION :

Since two decades, considerable amount of research work has been carried out in the area of

colon targeting. CDDS offers potential therapeutic benefits to patients in term of both local

and systemic treatment. Although the surface area in colon is low compared to small

intestine, this is compensated by the markedly slower rate of transit. Various approaches



described above are quite promising and further improvments are required to achieve the high

bioavilabiltiy and safe delivery of drugs to the colon.

REFERENCES:

1. Philip AK, Philip B, Colon targeted drug delivery system: a review on primary and novel

approaches. Oman Medical Journal. 2012; 25(2): 79-87.

2. Oluwatoyin AO, John TF. In vitro evaluation of khaya and albizia gums as compression

coating for drug targeting to the colon. J Pharma Pharmacol. 2005; 57: 63-168.

3.Akala EO, Elekwachi O, Chase V, Johnson H, Marjorie L, Scott K. Organic redox initiated

polymerization process for the fabrication of hydrogel for colon specific drug delivery, Drug

Dev Ind Pharm. 2003; (29): 375.

4. Bansode AS, Athare AB, Kasture VS, Kendre PN. Colon targeted drug delivery system:

An Overview. Int. Imperical Journal of Pharmaceutics and Cosmetology. 2012; 2(2): 1-7.

5. Reddy RB, Malleswari K, G. Prasad and G. Pavani. Colon tageted drug delivery system: A

Review. Int. Journal of Pharmaceutical Science and Research. 2013; 4(1): 42-54.

6. Bussemer T, Otto, Bodmeier IR. Pulsatile Drug Delivery Systems. Crit. Rev. There. Drug

Carrier System. 2003, (18): 433-458.

7. Mahale NB, Hase DP, Bhujbal SS, Gaikwad SN, Chaudhari SR. Colon specific drug

delivery system: A Review. Int. Journal of Pharmaceutical research and development. 2013;

4(11): 56-64.

8. Chan RP, Pope DJ, Gilbett AP, Sneta PJ, Baron JH and Bennardjones JF. Studies of Two

Novel Sulphasalazine Analogs I.P. Salazide and Balsalazide. Digestive Diseases Sciences.

1983; (28): 609-716.

9. Sinha VR, Kumria R. Polysaccharide matrices for microbially triggered drug delivery to

the colon, Drug Dev Ind Pharm. 2004; (30): 143.

10. Sinha VR, Kumria R. Microbially triggered drug delivery to the colon. Eur. J. Pharm. Sci.

2003; 18(1): 3-18.

11. Kumar R, Patil MB, Patil SR, Paschapur MS. Polysaccharides based colon specific drug

delivery: A review. Int. J. PharmTech Res. 2009; 1(2): 334-46.

12. Singh BN. Modified-release solid formulations for colonic delivery. Recent Pat. Drug

Deliv. Formul. 2007; 1(1): 53-63.

13. Pawar KS, Pawar SP, Patel VA. Microbial polysaccharidases in colon specific drug

delivery. Int. J. Pharm. Sci. Rev. Res. 2011; 6(2): 188-96.



14. Brahmanakar BM, Jaiswal SB. Biopharmaceutics and pharmacokinetics to controlled

release medication of oral site specific/colon DDS,1995; 457.

15. Reddy MS, Sinha RV, Reddy DS. Colon targeted systems. Drugs Today, 1995; 35(7):

537.

16. WU, Mcginity C, JW. Non-traditional plasticization of polymeric films. Int. J.Pharm.

1999; 177, 15–27.

17.Flory, P.J. (ED.). Principles of Polymer Chemistry. Cornell University, Ithaca, New York,

1953.

18. patel Asha-Colon Targeted drug delivery system: A review. Journal of Pharmaceutical

and Bio scientific research 2011; 1(1) :37-49.

19. Aurora J, Naresh T and Pathak V. Colonic drug delivery challenges and opportunities

.Pharmaceutical Research and Development.

20. Vijay- Novel approaches for colon specific drug delivery. Phama info.net.

21. Mundhe VS, Dodiya SS. Review Article: Novel Approach for Colon Targeted Drug

Delivery. Indo American Journal of Pharmaceutical Research. 2011; 3:158-173.

22. Takaya T, Niwa K, Muraoka M, Ogita I, Nagai N, Yano R, Kimura G, Yoshikawa Y,

Yoshikawa H, Takada K. Importance of dissolution process on systemic availability of drugs

delivered by colon delivery system. J Control Rel. 1998; 50 (1-3): 111-122.

23. Muraoka M, Hu Z, Shimokawa T, Sekino S, Kurogoshi R, Kuboi Y, Yoshikawa Y,

Takada K. Evaluation of intestinal pressure-controlled colon delivery capsule containing

caffeine as a model drug in human volunteers. J Control Rel. 1998; 52(1-2): 119-129.

24. Jeong Y, Ohno T, Hu Z, Yoshikawa Y, Shibata N, Nagata S, Takada K. Evaluation of an

intestinal pressure-controlled colon delivery capsules prepared by a dipping method. J

Control Rel. 71(2): 175-182.

25. Hay DJ, Sharma H, Irving MH. Spread of steroid containing foam after intrarectal

administration. Brit Med J. 1979; (1) 1751-1753.

26. Yang L, James S, Joseph A. Colon specific drug delivery new approaches and in vitro/ in

vivo evaluation. Int J Pharm 2002; 235:1 -15.

27. Ahmed IS. Effect of simulated gastrointestinal condition on drug release from

pectin/ethyl cellulose as film coating for drug delivery to the colon. Drug Dev Ind Pharm.

2005; 31(4-5): 465-470.

28. Gazzainga A, Busetti C, Morol, Crimella T. Int Symp Control Release Bioact Materials

1995; 22:242.



29. Danda S, Chandan KB. COLON TARGETED DRUG DELIVERY – A REVIEW ON

PRIMARY AND NOVEL APPROACHES. 2013; 4(3): 1174-1183.

30. Prathap M, Gulshan MD , Rama Rao. COLON: TARGETED DRUG DELIVERY

SYSTEM – A REVIEW. International Journal of Research in Pharmaceutical and Nano

Sciences. 2014; 3(5): 429 – 437.

31. Philip AK, Philip B. Colon Targeted Drug Delivery Systems: A Review on Primary and

Novel Approaches. OMAN MEDICAL JOURNAL. 2010; 25: 70-78.

32. kumar JR, Selvadurai M, Sokkalingam AD and Umadevi SK. A Novel Drug Delivery

Systems Of Colon Targeted : A Review J. Pharm. Sci. & Res. 2013; 5(2): 42 – 47.

33. Gupta VK, Gnanarajan G, Kothiyal P. A Review Article on Colonic Targeted Drug

Delivery System. THE PHARMA INNOVATION. 2012; 1(7).

34. Cherukuri S, Reddy CS, Neelaboina VP, Reddipalli S, Komaragiri K. COLON SPECIFIC

DRUG DELIVERY SYSTEMS: A REVIEW ON APPROACHES WITH CURRENT

TRENDS. PHARMACEUTICAL INTERNATIONAL RESEARCH JOURNAL OF

PHARMACY. 2012; 3 (7).

35. Sharma A, Jain KA. COLON TARGETED DRUG DELIVERY USING DIFFERENT

APPROACHES .International Journal of Pharmaceutical Studies and Research .2010; 1(1):

60-66.

36. Kumar V, Verma S, Mishra DN, and Singh SK. NOVEL APPROACHES IN COLON

TARGETED DRUG DELIVERY SYSTEM. Bulletin of Pharmaceutical Research. 2012;

2(1): 26-33.

37. Rangari NT, Puranik PK. Review on Recent and Novel Approaches to Colon Targeted

Drug Delivery Systems. International Journal of Pharmacy and Pharmaceutical Research.

2015; 3(1).

38. Hita V, Singh R and Jain SK. Colonic Targeting of Metronidazole using Azo Aromatic

Polymers, Development and Characterization Drug delivery. 1997; 4: 19-22.

39. McLeod AD, Friend DR and Toma NT. Glucocorticoid-Dextran Conjugates As Potential Prodrugs

for Colon Specific Delivery-Hydrolysis in Rat Gastrointestinal Tract Contents. J Pharm Sci. 1994;

83(9): 1284-1288.

review on-colon targated drug delivery system. rpa1516254015.pdfdrug delivery to the colon is...

Documents