Formulation of a chitosan multi-unit dosage form for drug delivery to the colon

Abstract

In some diseases it is preferable that the drugs used in their treatment are released in the colon. The colon is also suitable for systemic delivery of a variety of drugs. A variety of systems have been developed for the purpose of achieving colonic targeting. These approaches are either drug-specific (prodrugs) or formulation specific (coated or matrix preparations) and depends on the pH, transit time and pressure or bacteria in the colon. Different polymers, like chitosan, have been evaluated for their susceptibility to degradation by these bacterial enzymes. Chitosan is considered a good candidate for bacterial degradation and is widely available at low cost and has favourable biological properties. To investigate the influence of formulation factors on the properties of chitosan minitablets, it was necessary to ensure that the chitosan had satisfactory powder flow characteristics to ensure uniform compression in the tablet press and to prevent unacceptable variation in the tablet properties such as weight, thickness, disintegration and strength. Moisture content of the powder, particle size and the inclusion of glidants had an effect on the flowability and it could be improved from a composite flow index value of 32.7 to a value of 58.8. The compressibility of chitosan is very poor and different factors that might influence it, was investigated. Compression forces of between 15 and 20 bar resulted in tablets with acceptable physical characteristics. An increase in moisture content, using the powder fraction > 212 ym as well as a decrease in powder weight resulted in tablets with a higher tensile strength. Lower compression forces resulted in tablets that are extremely porous. This suggests that the chitosan can only be compressed at high compression forces which are difficult to obtain using a standard tablet press. The standard tablet press was therefore modified to fill more powder in the die and generate higher compression forces. Minitablets were compressed and the dissolution of isoniazide from these tablets was investigated. Varying the punch depth or the compaction of the powder did not result in the desired slower release of the drug as a result. The porosity of the tablets compressed at all the punch depth settings and compaction percentages was probably too high to have an effect on the wettablity of the tablets and as a result on the dissolution of the isoniazide from the tablets. The inclusion of excipients such as citric acid (an organic acid which would lower the pH in the tablet, allowing the chitosan to form a gel) and pectin (which would form an insoluble complex with the chitosan) into the formulation delayed the dissolution of the isoniazide from the minitablets. Coating of the minitablets with an enteric coating (Eudragit S ®) initially delayed the dissolution of the isoniazide and would protect the tablets from the harsh environment of the stomach so that the tablets will reach the colon and release the drug.