Vipin Bansal
1, A, Rishabha Malviya
2, B, C, E, Tanya Malaviya
3, D,
Pramod Kumar Sharma
2, FNovel Prospective in Colon Specific Drug Delivery System
1 Research Associate, FR&D, Akums Drugs and Pharmaceuticals Ltd, Haridwar, UK, India2 Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India 3 Department of Botany, University of Allahabad, Allahabad, Uttar Pradesh, India
A – research concept and design; B – collection and/or assembly of data; C – data analysis and interpretation; D – writing the article; E – critical revision of the article; F – final approval of the article
Abstract
This review deals with the targeting of drugs to the lower gastrointestinal tract i.e. colon. Colonic drug delivery becomes important for localized action as well as for improved systemic availability of peptide and proteins. Drugs which have absorp-tion window in the colonic region have been targeted using different novel technologies. pH sensitive polymers and prodrug based formulation have been used for the delivery of drugs into the colon. Different natural polymers have been used suc-cessfully for the delivery of drugs into the colon. Natural polymers are less toxic, biodegradable and easily available with a wide range of molecular weight and varying chemical compositions. One of the supporting properties associated with these polymers is that natural polymers can be used as approved pharmaceutical excipient (Polim. Med. 2014, 44, 2, 109–118).
Key words: targeted drug delivery, colonic delivery, natural polymer, colonic bacteria.
Polim. Med. 2014, 44, 2, 109–118 © Copyright by Wroclaw Medical University ISSN 0370-0747
REVIEWS
Oral administration of conventional dosage forms normally dissolves in the gastrointestinal fluid and then the absorption of drugs primarily depends upon physi-cochemical characteristics of the drug. Conditions be-come critical when a drug needs to be delivered only to the colon or when a drug needs to be protected from the pH and enzymatic environment of upper gastroin-testinal tract. Colon targeted drug delivery can be de-fined as drug delivery into the lower gastrointestinal part known as the colon [1, 2].
Formulations that deliver drugs into the colonic re-gion rather than the upper GI tract offer a number of advantages. In certain conditions, oral delivery of drugs to the colon is valuable in the treatment of certain dis-eases, such as ulcerative colitis, Crohn’s disease, carci-nomas, infections and colon cancer [3].
The colon is attracting interest as a site where poorly absorbed drug molecules may have improved bioavailability. The colon is a specific part of the body that contains numerous bacteria. Prodrugs and formu-lations that are degraded by the action of colonic bacte-rial enzyme are promising in their use for the delivery of drug into colon. Colonic drug delivery has a
promis-ing interest for drugs that are actpromis-ing as a substrate for cytrochrome P450 3A, as an activity of these class of enzymes are comparatively lower in the colonic part. Drug targeting to the colon for delayed absorption is also effective in the chronotherapy of diseases such as asthma, inflammation, hypertension, arthritis or car-diac arrhythmias[2, 4].
Advantages and Disadvantages
of Colon Targeting
Colon targeting is recognized to possess several clinical advantages for drugs that are destroyed in the stomach by stomach acid and/or metabolized by pan-creatic enzymes. Colon targeting provides better patient compliance due to the reduction in dose and dosage fre-quency. Localized treatment of colonic pathogens, such as colorectal cancer, ulcerative colitis, and Crohn’s dis-ease, is more effective with the delivery of drugs to the infected area[1, 2, 4].In some disease cases, pH of the GIT changes significantly and so a pH dependent system
releases drugs in a different manner e.g., in inflamma-tory bowel disease, the pH of the colon decreases than normal pH. Although pH dependent polymer system can be able to protect formulations in the upper gastro-intestinal tract, it may start to dissolve to a certain extent in the lower intestinal tract, and the desired site target-ing of formulations can be altered.The consideration of solubility of drug molecules is important for its colonic delivery. The colon contains relatively lower fluid con-tent than small intestine [5], so it becomes critical in the case of drugs having lower water solubility, leading to the poor dissolution of drugs. So in the case of such drug candidates, drugs are used in presolubilized form and generally targeted in the proximal colon, which has relatively more fluid than in the distal colon[6].
Peptides and Proteins
Peptides and proteins can be absorbed from the GIT, but the bioavailability of peptides and proteins by this route is too low, their oral absorption is limited by various factors such as the degradation of protein and peptides in the acidic medium of stomach, enzymatic degradation of proteins and peptides in the intestine, low mucosal permeability of proteins and peptides, ex-tensive first pass metabolism of therapeutic proteins and peptides. Drug targeting to the colon has proved to be an efficient site for the delivery of peptides and protein, as colon has a longer transit time (20–30 hrs), larger residence time, less enzyme (peptidase) activity, natural absorptive characteristics, and a high response to the absorption enhancers. Therapeutic molecules like insulin, calcitonin and vasopressin cytokine inhibitors and antibiotics (e.g., nisin) may be delivered systemi-cally through colonic absorption. Besides this vaccine, antigens can also be delivered systemically through the colon, as it is rich in lymphoid tissue [7, 8].
Design and Consideration of
Colon Targeted Drug Delivery
Dosage forms for colon targeted delivery are usu-ally delayed release and depend upon various factors such as:
a) If the formulation is intended for localized treat-ment, then its pathological conditions and disease pattern should be considered.
b) Biopharmaceutical and physicochemical properties of the active ingredient.
c) Release characteristics of drug.
d) pH gradient throughout the gastrointestinal tract. e) Transit of materials into and through the colon. f) Effect of diet on colonic transit.
g) Colonic bacteria.
Criteria for Drugs Selection
The best Candidates for colon targeting are those which show less absorption from the upper part of GIT.
Approaches to Colonic Drug
Delivery through Oral Route
Colon targeted formulations are useful in the treat-ment of inflammatory bowel diseases and this type of tar-geting has been designed using the following approaches:
pH Dependent Delivery
In a healthy person, it has been observed that pH in-creases from the duodenum (pH= 6.6 + 0.5) to the termi-nal ileum (pH = 7.5 + 0.4), then decreases in the cecum (pH = 6.4 + 0.4), and again there is a slight increase in pH from the right to the left colon with a final value of 7.0 + 0.7. Drug release is triggered by a change in the local pH as the formulation passes the GIT and prevents drug dissolution until the formulation passes into the small intestine. Enteric polymers are generally used and they are insoluble in the contents of the stomach; it is very es-sential that pH dependent formulation should maintain their physical and chemical integrity during their passage through upper GIT and small intestine. Table 1 shows
Table 1. Enteric polymers and their threshold pH
Polymers Threshold pH
Poly vinyl acetate phthalate 5.0 Cellulose acetate trimellitate 5.5 Hydroxypropyl methylcellulose phthalate HP-50,
HP-55 and HP-55S
≥ 5.0 ≥ 5.5 Hydroxypropyl methylcellulose acetate succinate LF grade, MF grade HF grade ≥ 5.5 ≥ 6.0 ≥ 6.8 Cellulose acetate phthalate 6.0 Acrylic acid copolymer
Eudragit L100-55 ≥ 5.5 Eudragit L30D-55 ≥ 5.5 Eudragit L-100 ≥ 6.0 Eudragit L12,5 ≥ 6.0 Eudragit S-100 ≥ 7.0 Eudragit S12,5 ≥ 7.0 Eudragit FS30D ≥ 7.0
Hydroxyl propylethyl cellolose phthalate ≥ 4.5
the threshold pH of various enteric polymers used for intestinal targeting and Table 2 shows the list of some marketed formulations used in the treatment of inflam-matory bowel disease.
A simplest approach to design a pH dependent co-lon targeted delivery system is to prepare enteric coated granules. An enteric coating polymer has been used as a binder as well as a coating polymer for granules and these polymers also protect the release of the drug in the upper GI tract. By utilizing the knowledge of polymers and their solubility in different pH, the formulation can be designed for the targeted site. Acrylic acid polymers and cellulose derivatives are most commonly used pH dependent polymers for colonic delivery. There are var-ious forms and grades of Eudragit as a colon targeting polymer is available. Eudragit (RS 100 and RL 100) are copolymers of methacrylic acid and acrylic acid esters in different ratios. Both these copolymers are insoluble in water, but they hydrate in GI fluids independent of pH. RS grade of Eudragit is relatively less hydrophilic because it contains less percentage of quaternary am-monium groups in comparison to RL grade. Eudragit-L is an anionic, copolymer of methacrylic acid and methyl methacrylate, which dissolves above pH 6. Mesalazine tablets coated with EudragitL-100 are commercially available under the trade name in market as Claversal, Salofalk, Mesasal, and Rowasa. The use of Eudragit-S as a colon targeting polymer was first described in 1982. In one study, tablet containing 5-Amino-salicylic acid with barium sulphate was coated with Eudragit-S was analyzed. At the end of twelve hours, twenty tablets were in the stomach and four tablets were in the colon, while, at the end of twenty-four hours, all the tablets reached the colon [9]. A combination of Eudragit S100 and Eu-dragit L100 ensures the release of drug even if the pH of the GIT remains below 6.8 due to the alteration of pH in disease condition. In a study, 5-fluorouracil matrices were prepared to release the drug in the colonic region. In the formulation of matrices, glyceryl palmitostearate was used as the retardant. Prepared granules were in-corporated in capsules to target drug release in ileum.
Soravoot et al. prepared a formulation with the potential for site specific delivery to the colon. In this system, we see prepared the pH-erosion-controlled and pulsatile release based on compression-coatings of tab-let cores containing model drugs of varying solubility (acetaminophen, carbamazepine and chlorpheniramine maleate) with enteric polymer Eudragit L100-55 and
the extended release polymer ethylcellulose at differ-ent compression forces and tablet core: compression coat ratios. All drugs were released after a lag time at a higher pH in a pulsatile manner. The addition of eth-ylcellulose protects the release of the drug in the lower media and also enhances the lag time in higher pH-media because of a reduction in wettability, erosion of the compression-coatings. The lag time could also be increased by increasing the compression force and also by decreasing the core: compression coat ratio [10].
Karrout et al.described the effect of novel polymer-ic film coating for colon targeting. In this study, extru-sion spheronization technique was used to formulate 5-Aminosalicylic acid loaded beads and afterword these beads were coated with Nutriose: ethylcellulose blends in a different ratio. In this article, in vitro drug release studies were performed under various conditions, in-cluding fresh fecal samples of patients suffering from inflammatory bowel disease. The investigated nitriose polymer (starch derivative) in this study was FB type which is a mixture of glucose polymers having a num-ber average molecular weight in the range of 2000–4000 Dalton. It is partially hydrolyzed (10–15%) in the small intestine. Due to the incorporation of ethylcellulose in the formulation, dissolution of polymeric coating in the upper gastrointestinal tract was prevented. The release of drug from the formulation could effectively be pro-tected in the simulated upper GIT fluid, without effect of agitation and enzymes. But when prepared formu-lation interact with fecal samples of diseased patients (inflammatory bowel disease), the release rate was sig-nificantly increased and the drug was released in a con-trolled manner. This type of novel formulation can be easily adopted for in vivo correlation in diseased condi-tion [11].
Karrout et al. described the effect of novel polymeric films for the site-specific delivery of drugs to the colon of patients suffering from inflammatory bowel disease. In this study, starch derivatives responsive to various bacteria were blended with ethylcellulose. Prepared for-mulations were analyzed for water uptake and dry mass loss kinetics in simulating media (stomach, small intes-tine, colon, fresh fecal samples of diseased patients). In simulated media, polymers (ethylcellulose: Nutriose FB 06, ethylcellulose: Peas starch N-735 films) showed water uptake and mass loss kinetics, thereby showing an ability to protect the release of the drug from the prepared formulation in the upper GIT, and when the
Table 2. Marketed drug products for the treatment of inflammatory bowel disease
Drug Dose Trade Name Formulation
Budesonide 9 mg Entocort Eudragit-L coated beads
Mesalazine 0.8–2.4 g/day Asacol Eudragit-S coated tablet (dissolves at pH 7) Mesalazine 1–2 g/day Claversal, mesazal calitoflak, rowasa Eudragit-L coated tablet
prepared formulation comes in to contact with the fe-cal samples of inflammatory bowel disease patients, the release rate was significantly increased which is due to these starch derivatives being catalyzed by the enzymes produced by the colonic microflora, and the drug was released in a time-controlled manner. Furthermore, Nutriose may be beneficial for patient suffering from inflammatory bowel diseases due to its prebiotic poten-tial [12].
Enzyme Dependent Delivery
– Prodrugs
These systems are generally based on the enzy-matic activity of the microfloras present in the colon, such as bacteroides, lactobacillus, eubacterium, bifido-bacterium, peptococcus, clostridium etc., which secrete a wide range of enzymes such as b-glucuronidase, urea hydroxylase, a-arabinosidase, nitroreductase, azoreduc-tase, b-xylosidase, b-galactosidase, deaminase etc [13]. These enzymes are capable of metabolizing sub-strates such as carbohydrates (di, tri and polysaccha-rides), proteins etc., that are not degraded in the upper gastrointestinal tract. Site targeted delivery of protein and peptide have been carried out using azo linked polymers. Colon specific drug delivery using these polymers may cause some problems such as microbial degradation of azo crossed links polymers is generally slow, resulting in incomplete and irregular drug ab-sorption. Crohn’s disease and ulcerative colitis has been treated with salfa drug (Sulphasalazine). Sulphasalazine is split by bacterial azoreductase into 5-Aminosalicylic acid and Sulphapyridine in the colon. There are other formulations based on enzyme dependent drug deliv-ery, such as balsalatsine, olsalazine and ipsalatsine are
prodrugs contained 5-aminosalicylic acid [6]. Dextran-naproxen prodrugs containing ester linkage has been prepared to deliver drug into colon. This is based on the fact that esterase present in colon, degrade the ester linkage, resulting in drug release [1, 2, 14].
Azo linked formulations are stable in the upper gas-trointestinal tract, as azo linkage is unaffected by the chemical and enzymatic degradation in the stomach and small intestine, but due to its hydrophobic nature, its degradation by enterobacteria is slow [15]. Anoth-er limitation of azopolymAnoth-er based formulation is that origination of some harmful substance on long-term use. These limitations can be overcome by the use of natural polymer materials with glycosidic linkage[5].
Enzyme Dependent Delivery
– Coatings and Matrices
A number of naturally occurring polysaccharides are stable in the upper intestine but yet susceptible to hydrolytic degradation in the lower intestine, to release the drug at a specific site. Colonic microorganisms, present in colon, are taken into consideration during the development of colon targeted delivery systems. Anaerobic and aerobic microorganisms are present into the gastrointestinal tract of a human. Research has found that that small intestine contains mainly aerobic microorganism, while the large intestine contains an-aerobic. Most bacterial species are found in the proxi-mal areas of the large intestine, where energy sources are greatest. Carbohydrates metabolized in to short chain fatty acids and carbon dioxide by glycosidases and polysaccharidases are the major source of nour-ishment for microorganism. These polymers are easily available but most of them have a hydrophilic nature
Table 3. List of some prodrug evaluated for colon specific drug delivery with in vitro/in vivo performance
Carrier Drug Linkage Performance of the prodrug/conjugates
Glycine 5-ASA Amide linkage Prodrug was unaffected in the stomach and was hydrolysed by the cecal content to release 5-ASA
Sulfhapyridine 5-ASA Azo linkage Released in the colon, but associated with side effects due to sulpha-pyridine
5-ASA 5-ASA Azo linkage Released two molecules of 5-ASA
Glucuronic acid Naloxone Glucuronide
linkage It was given to the morphine dependent rat; it reverses the side effect caused by morphine without causing CNS withdrawal symp-toms because of activation in large intestine followed by resultant diarrheas which excreted the prodrug
Glucose/galactose/
cellobioside Prednislone, hydro-cortison, fludrocor-tisone
Glycosidic
link-age Prodrug undergoes some degradation in the upper GIT, increases in distal colon and maximum in cecal content. Galactose conjugates hydrolyzed faster than glucosides which is faster than cellobioside L-Alanine/
D-Alanine Salicylic acid Amide linkage L-Alanine conjugates hydrolyzed by colonic microbes to salicylic acids while D-Alanine conjugates show negligible hydrolyse thereby showing enantiospecific activity.
and gel forming ability. This reduces the penetration of enzymes into the polysaccharide matrix. Chitosan, pectin, guar gum, amylase, inulin, gellan gum etc have been applied as a carrier for colonic drug delivery. Pec-tin and amylose have film-forming properties and have been used as coating material for colon-targeted formu-lations[1, 2, 4, 14].
Time Dependent Delivery
(Pulsatile Drug Delivery)
Pulsatile drug delivery assumed to delay drug re-lease until the formulation reaches the colon. Time dependant systems release the drug after a specific pe-riod of time and mimic gastrointestinal transit time. As transit time for small intestine is 3–4 h, so a lag time of 5 h is generally observed sufficient for the movement of formulation from the mouth to the colon [1, 2, 4]. A colonic disorder significantly alters colonic transit time and so it requires special attention in formulation of such type of system. Different combinations of hy-drophilic and hydrophobic polymers have been used as coating material on solid formulations to formulate time dependant colonic delivery system. Swellable system has been produced to deliver the drug after specific period of time. This type of formulation uses hydrophilic poly-mer that swells when coming in the contact with water and releases the drug, based on gastric transit. Lag time can be adjusted by altering the thickness of the coating polymer. A combination of a water insoluble polymer (e.g. ethyl cellulose) and hydrophilic polymers (e.g. hy-droxypropyl methyl cellulose, hyhy-droxypropyl cellolose) has been used to produce time dependant system.
Novel Approaches for Colon
Targeting
Pressure Dependent Delivery
It is based on the relatively higher pressure of the luminal contents of the colon as compared to the up-per gastrointestinal tract, which is due to the up-peristaltic movement occurring in the colon. In the large intes-tine, the viscosity of the luminal contents increases due to the re-absorption of water resulting in increased intestinal pressure[27]. The intestinal pressure fur-ther increases due to peristalsis in the distal intestine, providing a potential means to trigger active ingredi-ent release from a formulation susceptible to pressure changes[1, 2, 5].
Colon Targeted Novel Delivery
System (CODESTM)
This system is a combination of pH dependent as well as microbially dependent drug delivery into the colonic part and thereby overcomes the limitation as-sociated with the pH sensitive formulations and time dependent systems [28]. In this system, an acid soluble coating (Eudragit E) was applied over the tablet core loaded with an active part lactulose, which was again coated with an enteric polymer (Eudragit L). The enteric coating material protects the tablet from the upper part of GIT and dissolves in the small intestine and when the tablet comes into contact with the colonic fluid, poly-saccharide (lactulose) was enzymatically degraded by
Table 4. Examples of colon targeted formulations
Drug Polymer(s) Remark Reference
5-Acetyl salicylic acid Alginates, Amylose Bacteria dependent/
Polysaccharide based 16
Indomethacin Chondroitin sulphate, Pectin Bacteria dependent/
Polysaccharide based 17
Dexamethasone Guar gum Bacteria dependent/
Polysaccharide based 18
Diclofenac sodium Chitosan Bacteria dependent/
Polysaccharide based 19 Diltiazem HCl Hydroxy propyl methyl cellulose acetate succinate (HPMCAS) Time dependent 20 Theophylline Hydroxy ethyl cellulose, ethyl cellulose, microcrystalline cellulose Time dependent 21
Pseudo ephedrine HCl Hydroxy propyl methyl cellulose Time dependent 22
Paracetamol Eudragit L 30 D-55 and Eudragit FS 30 D pH dependent 23
Diclofenac sodium and
5-ASA Eudragit L100 and S100 pH dependent 24
Prednisolone Eudragit S, Eudragit FS, Eudragit P-4135 F pH dependent 25
the colonic microfloras into organic acid[29]. Further organic acid decreases the pH around the formulation and subsequent drug release takes place due to the dis-solution of acid soluble coating.
Osmotic Controlled Drug Delivery
These types of systems can also be used to target the drug locally to the colon for the treatment of disease or to achieve systemic absorption. In this device, a semi permeable membrane containing an osmotic agent with the drug is used to deliver the drug into colonic region. An orifice is drilled through the membrane next to the drug layer. This membrane is then coated with an en-teric coated polymer to prevent the drug being released in the upper gastrointestinal tract. As this system enters into the small intestine, the enteric polymer dissolves due to the higher pH; water moves towards core, which increased the volume within the osmotic compartment, forcing the active agent out of the devices through the delivery [30].Role of Natural Polymers
in Colon Targeting
Natural polymers have been applied for the tar-geting of drugs into colon. Polysaccharide based for-mulation are quite common to fulfill the objective of site specific targeting. The most favorable properties of these materials are that they are already approved for use as a pharmaceutical excepient. These types of mate-rials are considered safe because they are derived from dietary fibers. Their hydrophilicity and so water solu-bility is a major problem in the formulation of colonic delivery of active substance. These materials are either soluble or prone to being soluble in the aqueous envi-ronment of GIT [1, 2, 4, 14].
Pectin has been used as a single polymer as well as with a combination of other polymers for colon tar-geted delivery. It was found that when pectin is used alone, it needed relatively large quantities to control the release of the drug through the core, while a combina-tion of polymers (pectin, chitosan and hydroxypropyl methyl cellulose) was proven to be very efficient in the colon targeting of tablets. Natural polymers such as pectin, inulin and xylan etc. are not digested in the GIT but they are fermented by colonic flora. The degrada-tion product consists of natural gases such as methane, carbon dioxide, hydrogen and short chain fatty acids. These products are nontoxic and so natural polysaccha-rides are generally better carriers for the colonic deliv-ery of drugs. Different natural polymers used for colon targeting were summarized in Table 5.
Polysaccharides Obtained
from Plants
Starch
It is a polysaccharide obtained from the grains of maize, wheat, rice, potato etc. It contains chemically two different polysaccharides, namely amylose and amylo-pectin in the ratio of 1:2. Amylose is water soluble and amylopectin is water insoluble, but swells in water. The α-1, 4-linkage present in both amylose and amylopectin is attacked by amylases, while α-1, 6-linkage present in amylopectin is degraded by glycosidase. Amylose poly-mer can be used as an enteric coated polypoly-mer and are irresponsive to pancreatic α-amylase, but susceptible to colonic microbial enzyme[31].
Cellulose
It is the most widely distributed plant polysaccha-ride. It forms the main constituent of the cell walls of plants. It consists of cellobiose units in a repeateted manner. In colonic region of human, anaerobic bac-teria produces endo- and exo-enzymes, some enzymes form complexes and these complexes are important for nutrition of microorganism as they degrade cellulose to form carbohydrate nutrients. Combinations of amylose and ethyl cellulose as coatings have been used for co-lonic drug delivery [32].
Table 5. Natural polymers used for colon targeting
Polymers Examples Diasaccharides Lactose Maltose Oligosaccharides Cellobiose Cyclodextrins Lactulose Raffinose Stachyose Polysaccharides Alginates Pectins Chitosan Chondroitin sulphate Dextran Inulin Xantham gum Guar gum Starch Tragacanth Locust bean gum Cellulose Arabinogalactan Amylase
Pectin
It is a complex polysaccharide found in the middle lamella of plant cells. They are obtained from the inner portions of the rind of citrus fruits or other vegetative matter, such as papaya, sun-flower etc. It is soluble in 20 parts of water, aqueous solution being viscous and mobile. It is almost degraded by the bacterial enzymes present in colon[33].
Inulin
Inulin is a naturally abundant polymer found in garlic, onion and artichoke. Inula is the chief source and it contains 40–50% of Inulin. Inulin is susceptible to Bifidobacteria found in colon. It has been used with Eudragit RS to deliver drug in to colon, inulin prevents drug release in upper gastrointestinal tract but ferment in presence of Bifidobacteria and Bacteroides to release drug in colon [34].
Locust Bean Gum (Carob Gum)
It is derived from the seeds of Ceratonia siliqua. It is translucent-white, opaque at the edge and is very difficult to break. It is insoluble in alcohol, but is in-completely dispersed in water at room temperature. It mainly contains D-galactomannan. It forms water-insoluble film which gets digested by the colonic micro-flora. It has been used successfully with different ratios of Chitosan for colonic delivery [35].Gaur Gum
It is the most commonly used polymer for colon targeting, obtained from the endosperm of the seeds of Cyamposis tetragonolobus [36]. It is colorless or yel-lowish-white coloured powder which rapidly swells in water. It is chemically composed of water-soluble and water insoluble parts. The water-soluble fraction con-stituting about 85% of the gum is known as guaran. It has a gelling property and shows degradation in the large intestine by the microbial enzymes. Gaur gum has been used as a carrier with drugs such as metro-nidazole, indomethacin, albendazole, mebendazole for colon targeting.
A colon targeted formulation using natural poly-saccharide, guar gum was evaluated in healthy human male volunteers, with gamma scintigraphic study us-ing technetium 99m-DTPA as tracus-ing agent. It was observed that only traces of technetium were released in the stomach and small intestine while the remainder was released in the colon.
Polysaccharides
from Animal Origin
Chondroitin Sulfate
Chondroitin sulphate is a water-soluble polysaccha-ride, can be used for colon targeting as it is digested by the enzymes secreted by the Bacteroides thetaiotaomi-cron and B. ovatus present in the large intestine [37].
Hyaluronic Acid
It is a biopolymer, concentrated in vitreous humor of eye and synovial fluid of articular joints. It constitute linear, unbranched, anionic disaccharide units consist-ing of glucuronic acid (GlcUA) an N-acetyl glucosamine (GlcNAc) cross linked by β-1, 3 and β-1,4 glycosidic linkage [38].
Chitosan
Chitosan is a functional copolymer consisting of 2-amino-2-deoxy-D-glucose units linked with β-(1 > 4) bonds. Chitosan has been used as polymer for colon specific delivery as it can ne degrade by colonic
mi-croflora[39]. M.L. Lorenzo-Lamosa et alprepared pH
responsive particulate contain diclofenac sodium, en-trapped in enteric coated microspheres. In vitro drug release study performed and no release was observed in gastric pH, while a continuous release was observed in the intestinal pH [19].
Polysaccharides Obtained
from Bacterial
Dextran
This polysaccharide is produced by growing bacteria on the substrate sucrose, structurally it is a linear chain of α-D glucose molecules, 95% of the chains consist of α-D (1-6). Commercially, it is obtained from Leuconos-toc mesenteroides, LeuconosLeuconos-toc dextranicum organisms of the family Lactobacillus. Dextrans are colloidal, wa-ter soluble and insoluble in alcohol. It is hydrolyzed by the dextranase and these enzymes are produced by the anaerobic bacteria present in the colon. Its esteric form is widely used for the colon targeting [40].
Cyclodextrins
These are oligosaccharides containing 6-8 glucose units linked through α-1, 4 glucosidic bonds. It remains intact during passage from upper gastrointestinal tract and get degraded in to monosaccharide in the presence
of colonic micro-organism [41]. These are poorly ab-sorbed from the GIT due to their size and hydrophillici-ty and degraded in the large intestine, it is possible to use as carrier for delivery of drugs in the small intestine.
Polysaccharides Obtained
from Algae
Alginate
It is a linear copolymer polysaccharide derived from seaweed, consisting of 1–4, linked d-mannuronic acid and l-glucuronic acid residues. Sodium salt of al-ginic acid is readily soluble in water forming a viscous colloidal solution and is insoluble in chloroform, alco-hol, ether and strong acids. Sodium alginates can be easily crosslinked with the interaction of calcium ion. Cross linking of alginate beads can be achieved by add-ing a sodium alginate solution into a calcium chloride solution. Dried alginate beads are nontoxic and swell to form controlled release systems when coming in con-tact with the dissolution fluid. Enteric-coated polymers can be coated on calcium alginate beads to achieve tar-geted drug release [42].
Polysaccharides from Fungal
Scleroglucan (Sclg)
It is a nonlinear polysaccharide consisting of a (1-3)-linked β-D glucopyranosyl units. Resistant to hydrolysis and constant viscosity even presence of more ions is advantageous for controlled release of drugs [43].
Drug Delivery Index of Colon-Specific Drug De-livery Systems: After the administration of single or multiple doses of prodrugs based colonic drug delivery, pharmacokinetic parameters are measured in terms of the drug delivery index. Drug delivery index is a rela-tive measurement of RCE (relarela-tive colonic tissue ex-posure to the drug) to RSC (relative amount of drug in blood. Relatively high value of drug delivery index indicates better colonic delivery. Absorption of drugs through the colonic region is preferentially monitored by a colonoscopy and intubation. Gamma scintigraphy is a common technique used to evaluate colon specific drug delivery systems. For in vitro - in vivo correlation conditions such as diet, physical stress, pH, volume of dissolution media, microbial activity, quality and quan-tity of enzyme should be taken in consideration. In vitro models used for colon targeted delivery are:
a) In vitro dissolution test: Colon targeted delivery of drugs cannot be justified by USP relating to pH, bacterial activity etc [44]. Dissolution
characteris-tics of colonic drug delivery can be carried out us-ing the USP apparatus type 1, i.e. basket method. Usually dissolution may be carried out at different pH to simulate various gastrointestinal regions. b) In vitro enzymatic tests valuation: This type of
evaluation is carried out by placing the prepared formulation in fermenter enriched with microflora such as Streptococcus faccium, B. ovatus etc. Fur-ther formulation incubates in fermenter containing Strectococcus faccium and B. ovatus. Drug release should be carried out in the presence of suitable an-imal cecal contents and enzymes. Drug released is depending on degradation of polymer in presence enzymes or cecal microflora.
c) In vivo evaluation: Animals like rats, dogs, guinea pigs has been used to evaluate colon targeted de-livery of drugs as they mimic in vivo conditions of a human gastrointestinal tract. Guinea pigs have been used as an experimental model for inflamma-tory bowel disease.
Future Prospects of Colonic
Drug Delivery
It has been observed that the concentration of co-lonic microflora altered in disease conditions. So the degradation profile of various natural polymers de-graded by colonic bacteria should be studied in its dis-ease state for future prospects. This will provide a new approach for the formulation of a colonic drug deliv-ery system. There is also a need to standardize in vitro methods for an evaluation of CDDS.
Conclusions
It has been concluded from the study that the co-lon is an interesting site for the delivery of acid labile drugs as well as proteins and peptides. There are several approaches for colon targeting, such as pH dependent, pressure dependent, enzyme dependent etc, but each of these approaches has certain limitation in terms of site specificity, toxicity, uncertainty pattern of drug release due to change in gastro-luminal pH or due to change in enzyme population. These limitations can be over-come by the use of natural polymers or a combination of polysaccharide with synthetic polymers. These types of combinations have the greatest potential for colon specific delivery in terms of site specificity and safety. This article has described the application of various polysaccharides for colon targeting that are non-toxic and that are selectively degraded in the colon. So, chal-lenges in the future will be to find the polysaccharide or its combinations to obtain an impermeable film coating that exhibits high microbial degradability in the colon.
Acknowledgement: Authors are highly grateful to the National Institute of Science Communication and Information Resources
(NESCAIR), New Delhi for providing library facility during the literature survey.
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Address for correspondence:
Rishabha Malviya Department of Pharmacy
School of Medical and Allied Sciences Galgotias University
Plot No.2, Sector 17-A
Yamuna Expressway, Greater Noida, Gautam Buddh Nagar Uttar Pradesh
India
E-mail: rishabha.malviya@galgotiasuniversity.edu.in Tel.: +91 94 503 521 85
Conflict of interest: None declared Received: 1.10.2013
Revised: 4.04.2014 Accepted: 7.04.2014
