Review
Polysaccharides in colon-specific drug delivery

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Abstract

Natural polysaccharides are now extensively used for the development of solid dosage forms for delivery of drug to the colon. The rationale for the development of a polysaccharide based delivery system for colon is the presence of large amounts of polysaccharidases in the human colon as the colon is inhabited 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. Various major approaches utilizing polysaccharides for colon-specific delivery are fermentable coating of the drug core, embedding of the drug in biodegradable matrix, formulation of drug-saccharide conjugate (prodrugs). A large number of polysaccharides have already been studied for their potential as colon-specific drug carrier systems, such as chitosan, pectin, chondroitin sulphate, cyclodextrin, dextrans, guar gum, inulin, amylose and locust bean gum. Recent efforts and approaches exploiting these polysaccharides in colon-specific drug delivery are discussed.

Introduction

Many protein and peptide drugs like insulin, cannot be administered through the oral route because of their degradation by the digestive enzymes of the stomach and the small intestine. Delivery of drugs to the systemic circulation through colonic absorption represents a novel mode of introducing peptides and protein drug molecules and drugs that absorb poorly from the upper gastrointestinal tract (GIT) as the colon lacks various digestive enzyme present in the upper GIT. Also, for treatments of local diseases of the colon like ulcerative colitis, Crohn's disease and colon cancer, drug targeting not only reduces the dose to be administered, but also reduces the incidence of possible adverse effects associated with these chemotherapeutic agents.

The various approaches used for targeting the drugs to the colon include, formation of a prodrug, multicoating time-dependent delivery systems, coating with pH-sensitive polymers, pressure dependent systems, and the use of biodegradable polymers.

A prodrug is a pharmacologically inactive derivative of a parent molecule that requires spontaneous or enzymatic transformation within the body to release the active drug moiety. For targeting drugs to the colon, drug is to be protected from the hostile environments of the stomach and small intestine (SI). This protection in the upper GIT is affected by conjugation with carrier moieties, forming prodrugs. These prodrugs undergo enzymatic cleavage in the colon and regenerate the drug. An example of such a prodrug, which is extensively used in Crohn's disease and ulcerative colitis is sulphasalazine (Riley and Turnberg, 1990). It consists of 5-aminosalicylic acid (5-ASA) linked via an azo bond to sulphapyridine (SP). This prodrug when given orally is minimally absorbed in the stomach and the small-intestine and largely reaches the colon, where the bacterial azoreductase cleaves the azo bond thereby releasing 5-ASA, the drug moiety from SP, which acts only as a carrier (Azad Khan et al., 1977). Glycosidic prodrugs (Friend and Chang, 1984, Friend and Chang, 1985, Friend and Tozer, 1992, Friend, 1995), dextran prodrugs (Harboe et al., 1989a) and cyclodextrin conjugated prodrugs (Hirayama et al., 1996) of various drugs have been developed for colon-specific drug delivery. Though these prodrugs provide site specific drug delivery, these are new chemical entities and detailed toxicological studies need to be performed before their use.

Time dependent formulations are designed to resist the release of the drug in the stomach with an additional non-disintegration or lag phase included in the formulation (which equals to the small intestinal transit time) and the release of the drug takes place in the colon. An example of such a system is Pulsincap® (MacNeil and Stevens, 1990). This capsule consists of a non-disintegrating body having an enteric coated cap. The enteric coated cap dissolves in the small intestine and a hydrogel plug swells to create a lag phase. This plug ejects on swelling and releases the drug from the capsule. The large scale manufacturing of these systems, however, needs a lot of technological advancement and skills. Another limitation of the time dependent release systems are the variation in the gastric emptying time and small intestinal transit time (Davis et al., 1984). But, due to the use of enteric coating over most of these systems, the large variation in gastric emptying is overcome by most of these systems. However, there is still likely to be a considerable variability in the in vivo performance of the timed release systems by virtue of the variations in small intestinal transit time.

The pH of the GIT is acidic in the stomach and increases in the small and large intestine. This pH variation in different segments of GI has been exploited for colon-specific delivery. Coating the drug core with pH-sensitive polymers e.g. Eudragit® (methyacrylic acid-methylmethacrylate copolymers) has been successfully used for colon drug delivery in Asacol®, Salofalc®. These polymers are insoluble in acidic media, but dissolves at a pH of 6 or more, thereby providing protection to the drug core in the stomach and to some extent in the SI releasing the drug in the colon. However, the pH of GIT is subject to both inter and intra individual variations, depending upon the diet, disease, age, sex and the fed/fasted state (Wilson and Washington, 1989, Rubinstein, 1990). But due to the simplicity of the formulation of this device many marketed preparations utilize this approach. On prolonged use, these polymers may accumulate in the body so the use of biodegradable polymers is essential.

Osmotic systems independent of gastric residence time and metabolism by bacterial flora have also been developed for colon delivery of drugs. These systems are essentially timed release systems. OROS-CT systems developed by Theeuwes et al. (1990) consist of a single or 5–6 units. These enteric coated push–pull units contain an osmotic push compartment and a drug compartment, both surrounded by a semipermeable membrane with an orifice. As the unit enters the SI, the enteric coating dissolves and the osmotic push compartment containing an osmopolymer and an osmotic agent swells. Swelling of the osmotic push compartment forces the drug gel out of the orifice. These systems can be programmed to delay the drug release for varying durations (Theeuwes et al., 1993).

Another strategy relies on the strong peristaltic waves in the colon that lead to a temporarily increased luminal pressure (pressure-controlled drug delivery). Pressure-sensitive drug formulations release the drug as soon as a certain pressure limit is exceeded. The pressure and the destructive force induced by peristaltic waves is certainly high in the distal part of the large intestine (Muraoka et al., 1998). However, little is known about the reproducibility of this pressure and the duration of this high-pressure phase (Leopold, 1999).

The upper part of GIT, i.e. the stomach and the duodenum has a microflora of less than 103–104 CFU/ml. These are mainly gram-positive facultative bacteria (Gorbach, 1971, Simon and Gorbach, 1986). The microflora of colon on the other side is in the range of 1011–1012 CFU/ml (Moore and Holdeman, 1975) consisting mainly of anaerobic bacteria, e.g. Bacteroides, Bifidobacteria, Eubacteria, Clostridia, Enterococci, Enterobacteria, etc. This vast microflora fulfils its energy needs by fermenting various types of substrates that have been left undigested in the small intestine, e.g, di- and tri-saccharides, polysaccharide etc. (Rubinstein, 1990, Cumming and Englyst, 1987). For this fermentation, the microflora produces a vast number of enzymes like β-glucuronidase, β-xylosidase, α-arabinosidase, β-galactosidase, nitroreductase, azoreductase, deaminase and urea dehydroxylase (Scheline, 1973). Because of the presence of these biodegradable enzymes only in the colon, the use of bacterial degradable 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 the stomach and the small intestine and are able to deliver the drug to the colon. On reaching the colon, they undergo assimilation by micro-organism (Potts et al., 1973) or degradation by enzyme (Huang et al., 1979, Swift, 1992) or breakdown of the polymer backbone (Ratner et al., 1988, Hergenrother et al., 1992) leading to a subsequent reduction in their molecular weight and thereby loss of mechanical strength. They are then unable to hold the drug entity any longer (Park et al., 1993).

Biodegradable polymers have been used (a) as a linkage to form a prodrugs with the drug moiety, (b) as a coating material to coat the drug core or (c) as an embedding media to embed the drug moiety in their matrices or hydrogels. Examples of such systems include azo polymers which are film forming and are used to coat the drug core. A synthetic polymer used to coat the drug capsule of insulin and vasopressin is a copolymer of styrene and hydroxyethyl methacrylate, cross-linked with 4-4′-divinylazobenzene and N,N′-bis (β-styrene sulphonyl)– 4,4′-diaminoazobenzene. (Saffran et al., 1986, Saffran et al., 1991). The azoreductase present in the colon degrades the coating and then releases the drug from the capsule. The use of such synthetic polymers, requires a more detailed toxicological studies.

The ability of natural polymers i.e. the polysaccharides, from algal origin (e.g. alginates), plant origin (e.g. pectin, guar gum) microbial origin (e.g. dextran, xanthan gum) and animal origin (chitosan, chondroitin) to act as substrates for the bacterial inhabitants of the colon together with their properties, such as swelling, film forming and their biocompatability, biodegradability invites their use as colon-carriers.

The purpose of this review is to attempt to discuss the use of such natural polysaccharides as colon-specific drug delivery system.

Section snippets

Polysaccharides

Polysaccharides are polymers of monosaccharides (sugars). They are found in abundance, have wide availability, are inexpensive and available in a variety of structures with a variety of properties (Hovgaard and Brondsted, 1996). They can be easily modified chemically and biochemically and are highly stable, safe, nontoxic, hydrophilic and gel forming and in addition biodegradable, which suggests their use in targeted drug delivery systems.

Problem encountered with the use of polysaccharides is

Conclusion

There is an increasing interest in targeted delivery of drug to the colon via the oral route. Targeting drugs to the colon has major advantages in the direct treatment of the local disease and also for allowing the possibility of using colon for systemic therapy since the residence time is more than 24 h. Currently, several strategies are being used for targeting the drug specifically to the colon viz. systems that are, pH dependent, time-controlled, pressure-controlled, prodrugs and those

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