INTRODUCTION:

Oral controlled release drug delivery system for colon have received considerable attention for a variety of reasons like pharmaceutical superiority and clinical benefits derived from the drug release pattern that are not achieved with a conventional drug delivery system [19].

Targeted delivery of drugs to the colon usually designed to achieve mainly four objectives. The positive outcomes can be, sustained delivery (a) reduce dosing frequency; (b) delay delivery of drug to the colon to achieve high local concentrations of drug in the treatment of colonic diseases; (c) lag delivery of drug to treat diseases chronotherapeutically ﬁnally, (d) to deliver drugs to a region that is less hostile metabolically. Further commercial beneﬁt is the extension of patent protection [22].

Colon speciﬁc drug delivery had attempted in a number of ways that mainly consider the changes in the physiological parameters throughout the gastrointestinal tract. There are various systems have been designed for colon speciﬁc drug delivery. These approaches include the use of prodrug approach, use of pH-sensitive polymers, bacterial-degradable polymers, hydrogels and matrices, and time dependent delivery systems [23].

Enteric-coated (pH-dependent) systems mostly used for colonic drug delivery and constitute the majority of commercially available preparations for colon targeting. However, a disadvantage of these systems is that the pH-difference between the small intestine and the large intestine not being very pronounced, hence these delivery systems do not allow reproducible drug release. Limitation of time dependent release systems is that they are not able to sense any variation in the upper GIT transit time. The in vivo variations in small intestinal transit time however, may lead to drug release in the small intestine [6, 21].

Therefore, a more convenient approach to site-speciﬁc drug delivery to the colon is by designing systems, which can sense the arrival of drug delivery system into the colon and release the drug upon activation. Such systems can formulate utilizing some speciﬁc characteristics of the colon in comparison to the further parts of the GIT. The gastrointestinal tract colonized by a variety microﬂora all along. The ﬂora becomes assorted and luxuriant in the colon. It is the presence of these microﬂora in the colon, which utilized for site speciﬁc delivery [6].

The use of naturally occurring polysaccharides (guar gum, Chitosan, pectin, chondroitin sulfate, dextran, etc.) is attracting lots of attention for drug targeting to the colon since these polymers of monosaccharides are found in abundance, have wide accessibility, are inexpensive and are available in a variety of structures with varied properties. Along with these advantages, the most important property of polysaccharide polymer is their biodegradability by colonic microflora. However, a disadvantage of these systems is that a substantial amount of drug may release in the small intestine before the delivery system arrives in the colon. To avoid premature release of drug one of the options to reduce water solubility of the polysaccharide was chemically modified them without affecting their biodegradability is important [1, 7, 20].

There are different techniques, which used for the modification of polymers to reduce its water solubility and swelling, which includes such as grafting, cross-linking, acetylation, formation of polyelectrolyte complex or by using water insoluble polymer. In this review, describes all these techniques.

NATURAL POLYSACCHARIDE POLYMER:

Natural polysaccharides comprehensively used for the development of colonic delivery of drugs. Biodegradable polymers are usually hydrophilic in nature and have swelling characteristic in acidic pH. Various bacteria present in the colon secrete several enzymes which can cause hydrolytic cleavage of glycoside bonds e.g. β-D-galactosidase, amylase, pectinase, β-D- glucosidase, dextranase, α-D-xylosidase [1, 10, 3] . The list of natural polysaccharide polymers had shown in table 1.

Table: 1 Natural Microbially degradable polymers

Class	Examples
Disaccharides	Lactose
	Maltose
Oligosaccharides	Cellobiose
	Cyclodextrins
	Raffinose
Polysaccharides	Alginates
	Arabinogalactan
	Arabinoxylan
	Chitosan
	Chondroitin sulfate
	Dextran
	Galactomnam (guar gum, locust bean gum)
	Inulin
	Pectin

NEED OF REDUCTION OF WATER SOLUBILITY AND SWELLING OF NATURAL POLYSACCHARIDE POLYMER :

Natural polysaccharides such as guar gum, Chitosan, pectin, chondroitin sulfate, dextran, etc. are the best carrier for colon specific drug delivery system [2]. These polymers having advantages like found in abundance have wide availability, are inexpensive, biocompatible, biodegradable and more site (colon) specific than other polymers such as Eudragit derivatives due to property of microbial degradation [3]. Along with these advantages these polymers having certain disadvantages such as water solubility and swelling in water characteristics in the upper GI tract (stomach and small intestine) when used for colon specific drug delivery system [3]. Due to this premature release of drug is occurring and ultimately drug loss occurs in the stomach and small intestine. Because of premature release of drug 100 % drug cannot be reach to the colon [10]. So to avoid the premature release of drugs and to deliver the maximum amount of drug to the colon reduction of solubility and swelling in water (as the maximum percent of water is present in the content of GIT) of natural polysaccharide polymer is important one [2, 7, 10].

METHODS:

Some possible methods of reduction of water solubility and swelling of polysaccharide polymer showed in fig 1.

Fig 1: Different method of reduction of water solubility and swelling of polysaccharide polymer

A. Graft copolymerization:

Graft copolymers are a special type of branched copolymer in which the side chains are structurally different from the main polymer chain. Graft copolymers consist of a long progression of one polymer with one or more branches of another polymer [17]. Grafting process is a convenient method to adjoin new properties to a natural polymer with minimum loss of the initial properties of the substrate [4].By grafting synthetic polymers, natural polysaccharides can transformed into highly customizable matrices with hybrid properties. It involves the attachment of polymer chains, usually a monomer, to the backbone polymer. A variety of monomers, such as acrylamide, acrylonitrile, methylmethacrylate and methacrylamide had grafted to several polysaccharides [13].

There are various methods of graft copolymer synthesis, which differ in the ways of creation of the free radical at the sites of backbone polymer. Conventionally, chemical free radical initiators (e.g. Ceric ammonium nitrate (CAN), high energy radiation (gamma rays ) or UV rays in presence of photo sensitizers are used for this purpose. Due to homopolymerization, in conventional grafting the grafting yield decreased [4, 12].

Microwave enhanced chemistry is based on the efficiency of the interaction of molecules in a reaction mixture (substrates, catalyst and solvents) with electromagnetic waves. By different heating rates under the two conditions, microwave or thermal, different product selectivity achieved [13]. Microwave irradiation signiﬁcantly reduces the use of toxic solvents as well as the reaction time [8]. It also ensures high yields, product selectivity and clean product formations [8, 13].

Water used as a solvent in the majority of the polysaccharide grafting reactions, as many polysaccharides are soluble in water [4, 17]. Good solvents for microwave heating have given in table 2. Under microwaves, copolymerization is the preferential reaction [13].

Table no: 2 Good solvents for MW heating

Sr. No.	Solvent	BP	Temperature Achieved	Pressure
1.	N, N Dimethyl formamide (DMF)	153	250	5
2.	Water	100	220	16
3.	Ethanol	78	180	16
4.	Methanol	65	107	17
5.	Acetonitrile	86	200	10
6.	Acetone	56	150	5
7.	Diethyl ether	35	135	4
8.	Dimethyl sulfoxide (DMSO)	189	250	5

Fig 2: Grafting reactions.

1. Grafting in aqueous solution:

Most polysaccharide grafting reactions carried out in aqueous medium [13]. Other reactants such as catalyst initiators and monomers may be miscible or immiscible in the polysaccharide solutions. It has been observed that under heterogeneous reaction conditions (one of the reactant is immiscible) the grafting is more productive and simplistic, as a heterogeneous condition of the reaction contents had signiﬁcant bang on the grafting yield [4].

Irradiating a reaction mixture in an aqueous medium by microwaves involves two key mechanisms: dipolar polarization of water molecules and Ionic conduction. The dielectric heating that ensues from the tendency of dipoles to follow the inversion of an alternating electric field induces energy dissipation in the form of heat [4]. This allows more regular repartition in reaction temperatures compared to conventional heating. For grafting in aqueous solution, mainly two approaches have used: (1) microwave assisted grafting and (2) microwave initiated grafting [4, 13].

Fig 3: Conventional method of synthesis of graft copolymer

1.1 Microwave assisted grafting:

In this process, the ions will produce by the addition of external redox initiators to the mixture, and their presence enhances the capability of the aqueous reaction mixture to convert the microwave energy to heat energy. Under the influence of microwave dielectric heating, the generation of free radicals from the initiators facilitates the grafting reactions [4, 8, 13].

Fig 4: Microwave assisted method of synthesis of graft copolymer

1.2 Microwave initiated grafting:

Initiators not used in microwave initiated grafting reactions. Hydroquinone used as a radical inhibitor for inhibiting the grafting reactions. In microwave conditions, the heating results from the dipolar relaxation of solvent and due to localized rotation polar functional groups of polysaccharides [4, 8, 13].

2. Grafting on solid support:

A number of the reactions carried out between supported reagents on solid mineral supports, in dry media by impregnation of reactants on solid supports. In microwave synthesis under such solvent-free (dry media) conditions, the reagents are reacted neat or are preadsorbed on a more or less microwave transparent support (clay, silica or alumina) or on a strongly absorbing (graphite) inorganic support. Such reactions are of importance as they allow the safe use of domestic microwave ovens leading to a clean, efficient and economical production [4, 13].

Fig 5: Microwave initiated method of synthesis of graft copolymer

B. Cross-linking of the gums:

A cross-link is a bond that links one polymer chain to another polymer chain. The bond can be covalent bonds or Ionic bonds. When the word cross-linking applied in the synthetic polymer science field, it generally refers to promoting a difference in the polymer physical properties. Natural gums being hydrophilic swell / soluble in the presence of dissolution media. Hence, there may be chances of the entrapped drug release prior to arrival of the drug at its site of absorption (colon). Thus, there is a need to reduce the enormous swelling / solubility of the gums by cross-linking [2, 5, 6].

Cross-linking of gums requires accessibility of active functional groups in their basic structure. Gums such as guar gum, cashew gum or sterculia gums that possess free alcoholic and/or carboxylic units look to be a good choice for modiﬁcation by cross-linking [2].

Fig 6: Cross-linking techniques

1. Cross-linking with glutaraldehyde:

Glutaraldehyde used broadly for cross-linking of polymers containing hydroxyl groups. It was justified that with an increase in the concentration of glutaraldehyde there was an increase in the Crosslink network and thus decrease in buffer uptake. Drying of the hydrogel to form discs introduce irrevocable changes in the hydrogel. Thus, it was observed that when discs were formed, it resulted in alter in the degree of swelling. However, large amounts of glutaraldehyde were required for the cross-linking reaction suggesting that the cross-linking efficiency was low. However, the cross-linked products retained the ability of a polysaccharide polymer to degrade in vitro [4, 5].

George and Abraham [2007] were prepared alginate guar gum hydrogels with different alginate to guar gum percent weight ratio. Guar gum solution was prepared; the required amount of alginate added and stirred well to form a uniform mixture. To this mixture glutaraldehyde was added to a ﬁnal concentration of 0.2% (v/v), blended, and precipitated (in 0.5% (w/v) CaCl₂) to form beads. The beads washed with distilled water to remove any residual glutaraldehyde and calcium chloride, and lyophilized it [24].

Soppirnath, Kulkarni, and Aminabhavi [2000] carried out another experiment on interpenetrating network microspheres of polyvinyl alcohol and guar gum. These microspheres cross-linked by using glutaraldehyde. The aldehyde groups of glutaraldehyde reacted with the hydroxyl groups of the polymers to form acetal cross-links. The IR spectra showed an analogous peak at 1251 cm -1. DSC studies showed an increase in δH value. This increase in the δH value recognized for the high amount of energy required to break the highly cross-linked polymeric network structure. Thus, it suggests the formation of a crystalline polymeric matrix due to increase cross-linking agent density. The crystalline nature of the polymeric matrix reduces its water uptake and decrease in molecular transport of liquid within polymeric matrices observed, which results in reduced swelling [25].

2. Phosphate cross-linking of natural gums:

According to Kabir et al. [2000] and Dulong et al. [2004] the high swelling characteristics of natural gums in matrices, which leads to burst, release does not make them suitable for delivering drugs to distal parts of the gut. Such high swelling prevented using phosphate cross-linking. Generally, phosphate cross-linked gums can prepared by dissolving trisodium trimetaphosphate (STMP) in sodium hydroxide solution (1 M, pH 11) at room temperature for 30 min, followed by addition of gum under continuous stirring. The dispersion stirred slowly to permit maximum swelling of the gum. Lastly, the mixture is poured into a Petri dish and dried. The dried hydrogel obtained, washed several times with distilled water to remove untreated STMP, gum, and other soluble agents and dried to constant weight [6, 26].

3. Cross-linking with ions:

Alginate is a well-known example of polysaccharide that can cross-link by Ionic interaction. Alginate is polysaccharide with mannuronic and glucuronic acid residues cross-linked by calcium ion. Cross-linking carried out at room temperature and at physiological pH. Bajpai, Saxena, and Sharma [2006] carried out an experiment on sodium alginates bead formation. Sodium alginate and carboxymethyl guar gum dissolved in distilled water at a concentration of 4% (w/v). The polymer solution was then added drop wise in the gelation medium (CaCl2 solution of deﬁnite composition (w/v), 250 ml) at room temperature. The beads, thus form, were cured in the gelation medium for 20 min and then taken out, washed with distilled water 2 and then allowed to dry to constant weight at 30 ^OC [5, 27] .

4. Miscellaneous methods:

4.1. Cross-linking with epichlorohydrin:

Silva, Feitosa, Maciel, Paula, andPaula [2006] carried out epichlorhydin cross-linking on cashew gum. Cashew gum mixed with sodium hydroxide solution (5 M, 2 ml) and distilled water until a homogeneous paste formed. Epichlorohydrin (0.4–0.86 ml) then added to the mixture and kneaded to afford proper homogenization. The mixture heated at 40 C for 24 h, followed by a second heating time of 15 h at 70^oC. The cross-linked gel washed with distilled water, dialyzed for 72 h against distilled water and ﬁnally freeze-dried [4].

4.2. Radiation-induced cross-linking:

Singh and Vashistha [2008] Sterculia gum and deﬁnite concentration of monomers dissolved in distilled water (10 ml). The reaction mixture irradiated with gamma rays in a 60 Co chamber (for 24 h with a total dose of 53.14 KGy). The polymers thus formed stirred for two hours in a mixture of distilled water and ethanol (1:1) to remove remaining soluble fractions, and then dried in an oven at 40^oC [4] .

C. Acetylation:

The major challenge of using pectin for development of modified drug formulation is to overcome its aqueous solubility, which may contribute to the undesirable premature release of the drug. Harika Puppala Satya Krishna et al. [2011] and Manish S. Bhatia et al. [2008] worked on the chemical modification of and characterization of pectin as drug release retardant and evaluation of drug delivery. The aim of their work was to modify pectin by limited acetylation of their hydroxyl groups to yield high ester pectin and to investigate its swelling and solubility as well as other evaluation parameter. The polysaccharide can modify by acetylation using acetyl chloride, phenyl acetyl chloride. They observed that the solubility and swelling of pectin reduced as the concentration of acetyl chloride increased [14, 16].

D. By polyelectrolyte complex formation:

Giselle F. Oliveira et al. Prepared multiparticulate system of Chitosan and pectin. Chitosan (CS) is a cationic polysaccharide and pectin (PC) is an anionic polysaccharide. Polyelectrolyte complex formed between these two polymers, which will able to provide colon-specific delivery of drug. Comparing the swelling profile of control samples [PC: CS: TC (Triamcinolone)] with those of samples containing enteric polymers (CAP: TC; HPMCP: TC), it is evident that the incorporation of enteric polymers drastically decreased the swelling degree in the simulated gastric juice, promoting a greater protection of the particles. The in vitro drug release studies showed that the addition of enteric polymers, CAP and HPMCP, to the PC: CS: TC particles resulted in higher control over drug release [28].

In another investigation, Gurpreet Kaur et al. Performed research on colonic delivery of Budesonide: evaluation of Chitosan-chondroitin sulfate inter polymer complex. Tablets prepared by using Avicel pH 102 as diluent and Eudragit L100-55 as binder were coated to a weight gain of 10% w/w employing aqueous mixtures containing Chitosan (CH) and chondroitin sulfate (CS). The interpolymer complex between CH and CS was characterized using Fourier transform infrared (FTIR) and differential scanning calorimetry (DSC) studies. The peaks (FTIR) and endothermic transitions (DSC) characteristic of interpolymer complexation observed to remain unaffected after sequential exposure of the films to pH 1.2 and pH 7.4 buffer. This proved the usefulness of these IPC films for colon delivery [9].

Jitendra R. Amrutkar and Surendra G. Gattani develop a single unit, site-specific drug formulation allowing targeted drug release in the colon. Matrix tablets prepared by wet granulation using cross-linked Chitosan (CS) and chondroitin sulfate (ChS) polysaccharides as binder and carrier. ChS used to form polyelectrolyte complexes (PEC) with CS. DSC and XRD indicated that the PEC has different thermal characteristics from CS or ChS. Systems formulated using CS as a binder found to protect the majority of drug release during the usual upper GIT transit time of 5 h. These tablets can also tolerate variation in upper GIT transit time, since the rate of drug release before onset into the colon remains retarded. The study confirmed that selective delivery of indomethacin to the colon could be achieved using cross-linked CS and ChS polysaccharides [15].

E. By Using Water Insoluble Polymer:

As polysaccharide polymers, having characteristics of solubility and swelling in water the use water insoluble polymer like ethyl cellulose may be useful for the reduction of soluble and swelling of the polymer into the water.

Youness Karrout et al were prepared and characterized novel types of polymer coated pellets of 5-Aminosalicylic acid (5-ASA). The pellets were as coated with different Nutriose: ethyl cellulose blends. Nutriose is a starch derivative, which preferentially degraded by enzymes secreted by the microﬂora in the colon. In vitro drug release from these systems measured under various conditions, including the exposure to fresh fecal samples from IBD patients (under anaerobic conditions). The newly developed Nutriose: ethyl cellulose coated pellets effectively suppresses the drug release in the upper GIT. In addition, as soon as the pellets came into the colon, the release rate signiﬁcantly increased and the drug released in a time-controlled manner. Novel polymeric ﬁlms coatings proposed based on Nutriose: ethyl cellulose blends allowing for the site speciﬁc delivery of drugs to the colon [11].

In another investigation Salunkhe Kishor Sahebrao et al., Developed colon targeted drug delivery system by using dextrin as a carrier for Albendazole. Matrix tablets containing various excipient and polysaccharide prepared. The matrix tablets evaluated for in-vitro drug release study. The matrix tablet containing dextrin as a carrier and ethyl cellulose as binder found to be suitable for targeting Albendazole for local action in the colon because of less amounts of drug release in the simulated gastric and intestinal fluid. Matrix tablets containing dextrin released 96-98 % of Albendazole in simulated colonic fluid with 4 % human fecal matter solution. The results of an in - vitro study indicate that matrix tablets containing dextrin, as carrier and ethyl cellulose as binder are most suitable to deliver the drug specifically in the colonic region as compared to matrix tablets of dextrin with another binder system [18].

CONCLUSION:

Colonic delivery of drug has been one of the drug deliveries, which is getting popular from last few years. Moreover, the current trend in colonic drug delivery is to deliver drug using microbially triggered drug delivery system. Microbially triggered delivery of drugs is possible by using natural polysaccharide polymer. Because of their biodegradability by colonic micro-flora (10 ¹⁴), they are more site specific than any polymer.

The water solubility and swelling of these polysaccharide polymers limits their use. If we are able to control their water solubility and swelling then it is possible to deliver maximum amounts (100 %) of the drug in the colon. Their water solubility and swelling can control by modifying polymer chemically or physically or using different polymer blends. The possible ways to limit their water solubility by grafting, cross-linking, acetylation, by forming a polyelectrolyte complex or by using water insoluble polymer. This is the new area for research in relation to colon specific drug delivery system.

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Received on 23.01.2013 Modified on 10.02.2013

Research J. Pharm. and Tech. 6(5): May 2013; Page 447-453