COLON DRUG DELIVERY SYSTEM: A RECENT CONVENTIONAL AND NOVEL APPROACH

About Author:
Mr. Ripal Mistry
M.pharm
Indubhai Patel College Of Pharmacy & Research Center, Dharmaj
rx.ripalmistry@gmail.com

Abstract:
Colon-targeted delivery of drugs has recently gained importance in addressing specific needs in the therapy of colon based diseases. Many techniques have been tried for the development of colon targeted drug delivery systems. The colon is a site where both local and systemic delivery of drugs can take place. Local delivery allows topical treatment of inflammatory bowel disease. However, treatment can be made effective if the drugs can be targeted directly into the colon, thereby reducing the systemic side effects. This review, mainly compares the primary approaches for CDDS (Colon Specific Drug Delivery) namely prodrugs, pH and time dependent systems, and microbially triggered systems, which achieved limited success and had limitations as compared with newer CDDS namely pressure controlled colonic delivery capsules, CODESTM, and osmotic controlled drug delivery which are unique in terms of achieving in vivo site specificity, and feasibility of manufacturing process.

REFERENCE ID: PHARMATUTOR-ART-1855

Introduction:
Targeted drug delivery to the colon would ensure direct treatment at the disease site, lower dosing and fewer systemic side effects.

The colon specific drug delivery system (CDDS) should be capable of protecting the drug en route to the colon i.e. drug release and absorption should not occur in the stomach as well as the small intestine, and neither the bioactive agent should be degraded in either of the dissolution sites but only released and absorbed once the system reaches the colon.

The peptidase activity in the large intestine is significantly lower than that in the stomach and the small intestine and the colonic transit time is much longer than that of the upper GI tract.This allows the delivery of unstable peptide drugs and drugs with a low permeability to this lower intestinal region.

 

Figure 1: Main features of the colon

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

Targetsites	Disease conditions	Drug and active agents
Topical Action	InflammatoryBowelDiseases,Irritable bowel disease and Crohn’s disease. Chronic pancreatitis	Hydrocortisone, Budenoside, Prednisolone, Sulfaselazine, Olsalazine, Mesalazine, Balsalazide.
Local Action	Pancreatactomy,  cystic fibrosis, Colorectal cancer	Digestive enzyme supplements 5-Flourouracil
Systemic Action	To prevent gastric irritation To prevent first pass metabolism of orally ingested drugs Oral delivery of peptides Oral delivery of vaccines	NSAIDS Steroids   Insulin Typhoid

Table 1: Colon targeting diseases, drugs and sites.

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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.

Criteria for Selection of Drug for CDDS :

• The best Candidates for CDDS are drugs which show poor absorption from the stomach or intestine including peptides.
• The drugs used in the treatment of IBD, ulcerative colitis, diarrhea,and colon cancer are ideal candidates for local colon delivery.13 The criteria for selection of drugs for CDDS is summarized in Table 2.

Criteria	Pharmacological class	Non-peptide drugs	Peptide drugs
Drugs used for local effects in colon against GIT diseases	Anti-inflammatory drugs	Oxyprenolol, Metoprolol,	Amylin, Antisense
		Nifedipine	oligonucleotide
Drugs poorly absorbed from upper GIT	Antihypertensive and antianginal drugs	Ibuprofen, Isosorbides,	Cyclosporine, Desmopressin
Drugs for colon cancer	Antineoplastic drugs	Pseudoephedrine	Epoetin, Glucagon
Drugs that degrade in stomach and small intestine	Peptides and proteins	Bromophenaramine, 5-Flourouracil, Doxorubicin	Gonadoreline, Insulin,
Drugs that undergo extensive	Nitroglycerin and	Bleomycin, Nicotine	Protirelin,sermorelin, Saloatonin
first pass metabolism	corticosteroids
Drugs for targeting	Antiarthritic and	Prednisolone, hydrocortisone,	Somatropin,Urotoilitin
	antiasthamatic drugs	5-Amino-salicylic acid

Table 2: Criteria for selection of drugs for CDDS

• Drug Carrier is another factor which influences CDDS. The selection of carrier for particular drugs depends on the physiochemical nature of the drug as well as the disease for which the system is to be used.

• Factors such as chemical nature, stability and partition coefficient of the drug and type of absorption enhancer chosen influence the carrier selection. Moreover, the choice of drug carrier depends on the functional groups of the drug molecule.

• For example, aniline or nitro groups on a drug may be used to link it to another benzene group through an azo bond. The carriers, which contain additives like polymers (may be used as matrices and hydro gels or coating agents) may influence the release properties and efficacy of the systems

Approaches For The Colon Targeting
Several approaches are used for site-specific drug delivery.

[A]- Conventional approaches for CDDS
a) pH sensitive polymer coated drug delivery to colon
b) Delayed (Time controlled release system) release drug delivery to colon
c) Microbially triggered drug delivery to colon
(i) Prodrug approach for drug delivery to colon
(ii) Polysaccharide based approach for drug delivery to colon

[B]- Novel pharmaceutical approaches for CDDS
a. Pressure controlled drug delivery system (PCDCS)
b. CODES™ (A Novel colon targeted delivery system)
c. Osmotic controlled drug delivery to colon
d.Microparticulate systems

[A]- Conventional approaches for CDDS

a) pH sensitive polymer coated drug delivery to colon.

• This approach utilizes the existence of pH gradient in the GIT that increases progressively from the stomach and small intestine to the colon.
• 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.
• This pH differential principle has also been attempted for colonic delivery purposes.
• Use of pH-dependent polymers is based on these differences in pH levels. They do not allow to release the drug in stomach and remain intact and protect form formulation in the stomach and proximal small intestine.
• In fact, the pH in the distal small intestine is usually around 7.5, while the pH in the proximal colon is closer to 6. These delivery systems therefore have a tendency to release their drug load prior to reaching the colon.

Segment	pH
A.    Pre-prandial Stomach  Duodenum Upper jejunum Lower jejunum Upper ileum Lower ileum Proximal colon	1.8 6.0 6.5 6.8 7.2 7.5 5.5–6.5
B.     Post-prandial Stomach Duodenum Upper jejunum Lower jejunum Upper ileum Lower ileum Proximal colon	4 5.0 5.5 6.5 7.2 7.5 5.5–6.5

Table 3: pH of GIT

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To overcome the problem of premature drug release, a copolymer of methacrylic acid, methyl methacrylate and ethyl acrylate (Eudragit® FS), which dissolves at a slower rate and at a higher threshold pH (7–7.5), has been developed recently.

Polymers	Threshold pH
Eudragit® L 100 Eudragit® S 100 Eudragit® L-30D Eudragit® FS 30D Eudragit® L 100-55 Polyvinyl Acetate Phthalate Hydroxypropyl Methylcellulose Phthalate Hydroxypropyl Methylcellulose Phthalate 50 Hydroxypropyl Methylcellulose Phthalate 55 Cellulose Acetate Phthalate Cellulose Acetate Trimellate	6.0 7.0 5.6 6.8 5.5 5 4.5- 4.8 5.2 5.4 4.8 5.0

Table 4: Various pH dependent coating polymer

• Most commonly used pH-dependent coating polymers for peroral delivery are methacrylic acid copolymers, Eudragit L100 and Eudragit S100, which dissolve at pH 6.0 and 7.0 respectively.

• The combination of these two polymers in various ratios makes it possible to manipulate drug release within 6.0-7.0 pH range.

• Combination of polymers Eudragit S100 and Eudragit L100 ensures that the release of drug from formulation will occur even when the pH value of the GI tract does not reach more than 6.8.

It can made by two type :
A.Coating of the drug core with pH sensitive polymers
B.Embedding in pH-sensitive matrices

EUDRACOL®

• It is a colon-targeted, pH-triggered and sustained-release oral drug delivery technology for multi-unit dosage forms, for both local and systemic therapies.
• More robust delivery systems, more secure multi-particle systems proprietary drug delivery technology.

 

Figure 2: Structure of EUDRACOL®

EUDRACOL® is based on a multi-layer coating system providing drug protection in the gastrointestinal tract and controlled drug release in the colon

 

Figure 3: Working of EUDRACOL®

b) Delayed (Time controlled release system) release drug delivery to colon

• In these systems the release of the drug is decided by the transit time of a formulation in the GIT, which makes it challenging to develop a formulation that can achieve a precise drug release in the colon.
• It involves delaying the release of the drug until it enters into the colon.
• The time release systems are designed in such way that the site of delivery (i.e. colon) is not affected by the individual’s difference in the
• gastric emptying time, pH of the stomach and small intestine or the presence of anaerobic bacteria in the colon.
• The lag time in this case is the time requires to transit from the mouth to colon. A lag-time of 5 hours is usually considered sufficient since small intestine transit is about 3-4 hours, which is relatively constant and hardly affected by the nature of formulation administered.
• By selecting a suitable combination of controlled-release mechanisms, the drug release from these systems can be precisely programmed to produce predetermined lag phase.
• In general, pH-dependent (enteric coat) components are used for time released formulations of colonic delivery because the transit of a formulation in the GIT is largely influenced by the gastric emptying time.
• Colon-specific drug formulations relying on the time-dependent dissolution of basic polymer layers such as Eudragit® E and chitosan.

CAPSULE BASED SYSTEM : PULSINCAP

• Capsule based system consists of pulsincap system, which consists of an insoluble capsule body and swellable and degradable plugs made of approved substances such as hydrophilic polymers or lipids.
• The lag time is controlled by plug, which pushed away by swelling or erosion and drug is released as a pulse from the insoluble capsule i.e. Pulsincap®.

 

Figure 4: Working of Pulsincap

• A swellable hydrogel plug seals the drug contents in to capsule body. When this capsule body came in to contact with dissolution medium, the hydrogel plug swells, and after the lag time the plug pushed itself outside the capsule and rapidly released the drug.
• Various types of material used for formulation of swellable plug which include hydroxyl propyl methyl cellulose, poly vinyl acetate and poly ethylene oxide. The length of plug decides lag time. Plug material is generally made up of HPMC, polyvinyl alcohol, glyceryl mono oleate, pectin, polymethacrylates.

c) Microbially triggered drug delivery to colon

• The GIT contains a variety of microorganisms that participate in the metabolism of ingested material.
• The growth of the bacteria is regulated by gastric acids, peristaltic activity and microbial interaction including bacterial metabolic byproducts.
• The microflora of the colon is in the range of 1011 -1012 CFU/ mL. Almost 400 distinct bacterial species have been found.

 

Figure 5: Bacterial flora of the Human GI tract

• It consisting mainly of anaerobic bacteria, e.g. bacteroides, bifidobacteria,eubacteria, clostridia , enterococci, enterobacteria and ruminococcus, etc.

• This vast microflora fulfills its energy needs by fermenting various types of substrates that have been left undigested in the small intestine, e.g. di- and tri-saccharides, polysaccharides etc.

• For this fermentation, the microflora produces a vast number of enzymes like glucoronidase, xylosidase, arabinosidase, galactosidase, nitroreductase, azareducatase, 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 polymers shield the drug from the environments of stomach and small intestine and are able to deliver the drug to the colon.

Enzymes	Microorganism	Metabolic ReactionCatalyzed
Nitroreductase	E. coli, Bacteroids	Reduce aromatic and heterocyclic nitro compounds
AzoreductaseAzoreductase	Clostridia,  Lactobacilli,E. coli	Reductive cleavage of azo compounds
N-Oxide reductase, sulfoxidereductase	E. coli	Reduce N-Oxides and sulfoxides
Hydrogenase	Clostridia, Lactobacilli	Reduce carbonyl groups and aliphatic double bonds
Esterases and amidases	E. coli, P. vulgaris, B. subtilis, B. mycoides	Cleavage of esters or amidases of carboxylic acids
Glucosidase	Clostridia, Eubacteria	Cleavage of ‚ β-glycosidase of alcohols and phenols
Glucuronidase	E. coli	Cleavage of ‚ β-glycosidase of alcohols and phenols
Sulfatase	Eubacteria, Clostridia, Streptococci	Cleavage of O-sulfates and sulfamates

Table 5: Various metabolic reaction and their enzymes.

When it reaches the colon, they undergo degradation by micro-organism, or 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.

PRODRUG APPROACH

• Prodrug is a pharmacologically inactive derivative of a parent molecule that requires enzymatic transformation in the biological environment to release the active drug .
• Prodrug approach is an outcome of the covalent linkage of drug with carrier.
• The prodrug is designed to undergo minimal hydrolysis in the upper tracts of GIT, and undergo enzymatic hydrolysis in the colon there by releasing the active drug moiety from the drug carrier.
• The triggering mechanisms for the release of the drug in the colon can be decided by the type of linkage that is formed between the drug and the carrier.
• The enzymes like azoreductase, galactosidase, xylosidase, nitroreductase, glycosidase and deaminase are mainly targeted for colonic drug delivery.
• The prodrugs are hydrophilic and bulky as it minimizes their absorption from the upper GIT. Once the prodrug reaches to the colon, it is converted into a more lipophilic drug molecule that is then available for absorption

 

Figure 6: Design of Prodrug

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• It’s formulation depends upon the functional group available on the drug moiety for chemical linkage.
• The Drug Delivery Index (DDI) allows a quantification of the reduction in the drug dose and the systemic exposure observed after drug release specifically to the colon.
• It may be calculated using AUC and drug concentrations in blood and colonic tissues.

 

* On the basis of functional group the prodrug approach can be attained by

Approach	Basic features
Azo bond conjugate	The drug is conjugated with azo bond
Glycosiide conjugation	The drug is conjugated with glycoside
Cyclodetrin conjugation	The drug is conjugated with cyclodextrin
Dextran conjugation	The drug is conjugated with dextran
Amino acid conjugation	The drug is conjugated with amino acids
Polymeric prodrug	The drug is conjugated with polymer
Glucoronideconjugates	The drug is conjugated with glucurunates

Table 6: Pro drug

i. Azo bond conjugate

• Newer approaches are aimed at use of polymers as drug carriers for drug delivery to the colon.
• Both synthetic as well as naturally occurring polymers are used for this purpose. Subsynthetic polymers have been used to form polymeric prodrug with azo linkage between the polymer and drug moiety.
• Coating of peptide capsules with polymers cross linked with azoaromatic group has been found to protect drug from digestion in the stomach and small intestine.
• In this approach drug has been conjugated by azo bond. These azo compounds are extensively metabolized by the intestinal bacteria, by intracellular enzymatic components and extracellular reduction.
• The azo bond is stable in the upper GIT and is cleaved in the colon by azoreductases produced by the microflora.
• The use of these azo compounds for colon-targeting has been in the form of hydrogels as a coating material for coating the drug cores and as prodrugs.
• These have been found to be similarly susceptible to cleavage by the azoreducatase in the large bowel.
• Sulphasalazine, used for the treatment of IBD has an azo bond between5-ASA and sulphapyridine (SP). In the colon, the azoreductases cleavethe azo bond releasing the drug, 5-ASA and the carrier SP.

 

Figure 7: Figure: Hydrolysis of sulfasalazine (i) into 5-aminosalicylic acid (ii) and sulfapyridine (iii).

ii. Glycoside Conjugation :-

• This approach has been based upon the unique glycosidease activity of the colonic microflora.Certain drugs can be conjugated to different sugar moieties to form glycosides.
• The drug part forms aglycone and the sugar part forms glycone of the glycoside. These glycoside molecules are hydrophilic in nature thus these are impermeable to the biological membrane upon ingestion.
• They breakdown in to monomeric unit by the action of glycosidase enzyme, releasing the drug part from the sugar.
• However the presence of glycosidase activity in the small intestine could pose a problem in delivery of these conjugates to the large bowel but the transit time of the drug in small intestine, when compared to the large intestinal transit time, is short, and moreover, considering the time required for the hydrolysis of glycosidic bond, these conjugates can be expected to be good colon specific drug carriers.
• The major glycosidase enzymes produced by the intestinal microflora are β -D-galactosidase, α-Larabinofuranosidase, β-D-xylopyranosidase, and β–Dglucosidase.
• These glycosidase enzymes are located at the brush border and hence are accessible to substrate easily
• Drugs that can be targeted by this approach are: lucosides, galactosides, and cellobiosides of dexamethasone, prednisolone, hydrocortisone, and fludrocortisone.

iii. Glucoronide conjugates

• This approach has been based upon theconjugation of drug with glucuronats. The lower GIT secrete β-glucuronidase that deglucuronidate a variety of drugs in the intestine.
• This deglucuronidation process results in the release of the active drug again and enables its reabsorption.

iv. Amino acid conjugation

• This approach has been based upon theprinciple that the basic units of the amino acids i.e. -NH2 and –COOH are hydrophilic in nature, it reduces the membrane permeability of amino acids and proteins.
• Thus by increasing the hydrophilicity and chain length of the carrier amino acid and decreasing the membrane permeability of conjugate.

POLYSACCHARIDE

• Natural polysaccharides are extensively used for the development of solid oral dosage forms for colonic delivery of drugs.

• Biodegradable polymers are generally hydrophilic in nature and have limited  swelling characteristic in acidic pH.

• Linear polysaccharides remains intact in stomach and small intestine but the bacteria of human colon degrades them and thus make them potentially useful in colon targeted drug delivery systems.

• Use of naturally occurring polysaccharides is attracting lot of attention for drug targeting to the colon since these polymers of onosaccharides are found in abundance, have wide availability are inexpensive and are available in a verity of a structures with varied properties.

• Polysaccharides are the polymers of monosaccharides which retains their integrity because they are resistant to the digestive action of gastrointestinal enzymes.

• They can be easily modified chemically, biochemically, and are highly stable, safe, nontoxic, hydrophilic and gel forming and in addition, are biodegradable.

• These include naturally occurring polysaccharides obtained from plant (guar gum, inulin), animal (chitosan, chondrotinsulphate), algal (alginates) or microbial (dextran) origin.

* DEXRAN :

• Dextran is a polysaccharide consisting of α-1,6 D-glucose and side chain of α-1,3 D-glucose units
• Dextran contains a large number of hydroxyl groups, which can be easily conjugated to drugs and proteins.
• Dextran gets degraded by microbial enzyme dextranases, which is found in  the colon.
• This approach has been based upon polysaccharide nature of dextran that masks the drug in the upper GIT tract, the presence of dextranase in the colon leads to the delivery of drug to the colon.
• The dextranase activity is shown by anaerobic gram-negative bacteria, especially the Bacteroides, which are present in a concentration as high as 1011 per gram in colon.
• Dextran prodrug approach can be used for colon-specific delivery of drugs containing a carboxylic acid function (−COOH).
• NASIDS were directly coupled to dextran by using carboxylic groups of drug

 

Figure 8 : Structure of dextran

* CYCLODEXTRIN :

• Cyclodextrin is a cyclic oligosaccharide consisting of six to eight glucopyranose units joined by α-(1→4)  glucosidic linkage.
• Cyclodextrins consist of six, seven or eight glucose monomers arranged in a ring shape and these are denoted as α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, res