Colonic drug delivery of 5-fluorouracil: an in vitro evaluation

Abstract

Compression coating has been found to be useful for colonic drug delivery. The aim of the present investigation was to design a formulation with a considerably reduced coat weight and gum concentration for colonic delivery of 5-fluorouracil for the treatment of colorectal cancer. Rapidly disintegrating core tablets containing 50 mg of 5-fluorouracil were prepared and compression coating with 175 mg of granules containing a mixture of xanthan gum (XG) and guar gum (GG) in varying proportions was done. With this coat weight, a highly retarded drug release was observed. After 24 h of dissolution the mean percent drug release from the compression coated XG:GG 20:20, 20:10 and 10:20 tablets were found to be around 18±1.23%, 20±1.54% and 30±1.77%, respectively. So, the coat weight was further reduced to 150 mg. It was observed that reduction of coat weight did not affect the initial drug release rate in simulated upper gastrointestinal tract (GIT) conditions. At the end of 24 h of dissolution the amount of drug released increased to 25±1.22%, 36.6±1.89% and 42.6±2.22%, respectively in XG:GG 20:20, 20:10 and 10:20 tablets. Studies of XG:GG (10:20) tablets in presence of colonic contents showed an increased cumulative percent drug release of 67.2±5.23% in presence of 2% cecal content and 80.34±3.89% in presence of 4% cecal content after 19 h of incubation.

Introduction

Site specific delivery of drugs to the receptor site has the potential to reduce side effects and to increase pharmacological response. One of the seemingly interesting areas to target drugs through oral route for systemic drug delivery is the colon, the proximal part of the large intestine. Further, there are a number of local pathologies warranting direct release of drug in the colon. This will not only improve pharmacotherapy but also reduce the potential toxic or side effects. The treatment of disorders of the large intestine, such as irritable bowel syndrome, colitis, Crohn’s disease, colon cancer and infectious diseases where it is necessary to attain a high concentration of the active agent, may be efficiently achieved using colon specific delivery systems. Conventional oral dosage forms are ineffective in delivering drugs to the colon due to absorption and/or degradation of the active ingredient in the upper gastrointestinal tract (GIT).

Various approaches have been used for targeting the drugs to the colon including, formation of a prodrug, multicoating time-dependent delivery systems, coating with pH-sensitive polymers, pressure-dependent systems, and systems formulated making use of biodegradable polymers (Kinget et al., 1998). Every system has advantage as well as shortcoming. However, biodegradable systems formulated making use of naturally occurring polysaccharides are increasingly being developed (Sinha and Kumria, 2001a, Sinha and Kumria, 2001b, Sinha and Kumria, 2002). Natural polysaccharides remain undigested in the stomach and the small intestine and are degraded by the vast anaerobic microflora of the colon, for example, bacteroides, bifidobacteria, eubacteria, to smaller monosaccharides, which are then used as energy source by the bacteria. In an earlier study these were used in the from of binders in tablet formulation (Sinha and Kumria, 2002).

The present investigation is aimed at using these inexpensive, naturally occurring and abundantly available polysaccharides for colon delivery of 5-fluorouracil. An attempt was made to formulate a dosage form which consisted of biodegradable polysaccharides as the main constituent, showed minimal release of 5-fluorouracil in the tracts of the upper GIT and rapid release in the tracts of the colon.

5-Fluorouracil is a pyrimidine analogue and is the drug of choice for colon cancer (Calabresi and Chabner, 1992). It inhibits RNA function and/or processing and synthesis of thymidylate. It is administered parenterally since absorption after ingestion is unpredictable and incomplete (Hahn et al., 1975). Targeting of 5-fluorouracil to the colon in cases of colon cancer would not only reduce the systemic toxicity of the drug but would also show the desired action in a lesser dose.

Working on this rationale, a drug release-retarding ingredient falling under the category of polysaccharides, i.e. xanthan gum (XG), which is known to retard drug release considerably, was selected for the study (Talukdar and Kinget, 1995, Sujja-areevath et al., 1998). Guar gum (GG) another polysaccharide being widely used for colon targeting was selected as the other ingredient. Guar gum alone has earlier been used in colon specific drug delivery as matrix forming material and as a compression coat (Wong et al., 1997, Rama Prasad et al., 1998, Krishnaiah et al., 1999). Xanthan gum is known to have a greater drug release retarding property and synergistically enhanced gel properties in presence of galactomannan gums like guar (Melia, 1991). So a combination of these gums was used. This mixture of gums was evaluated for its drug release retarding properties under simulated gastrointestinal tract (GIT) conditions. This mixture was proposed to retard drug release more significantly in conditions of the upper GIT but still retain biodegradability due to the presence of guar gum. Presence of xanthan gum in the compression coat would not only retard the initial drug release from the tablet but due to a higher swelling of xanthan gum the susceptibility of the compression coat to undergo degradation by the microflora would increase as higher the swelling, more the surface area available for microbial action. Starch, which is a usual filler in the tablet dosage form was used as an excipient.