Influence of modified release excipients on Ketoprofen release from Chitosan particles

Abstract

Controlled release dosage forms are of increasing importance in the pursuit for patient compliance. Specialized controlled release dosage forms with the ability to shield drugs from the harsh environment of the stomach often require additional steps in the production of the formulation, thereby increasing the cost associated with production. This high cost of production is of economic importance and often outweighs the immediate benefits to the patients, especially in third world countries. It would therefore be favorable if a method could be devised by which such specialized controlled release dosage forms can be produced by simple means. <br><br> Chitosan is a polymer, of natural origin, commonly used in the pharmaceutical industry. Chitosan has been, compared to traditional excipients, shown to have superior characteristics and is especially flexible in its use. It is a biocompatible, biodegradable, and muco-adhesive polymer. Chitosan also has anti-ulcer and antacid activities (Acikoz et al, 1995). Chitosan was found to be an excellent candidate for the production of beads via the inotropic gelation technique. This technique was chosen above others as being simple, and gives reproducible results. Chitosan is soluble in acetic conditions. Not only does this pose a problem with possible high release of drug in the acidic regions of the stomach, but also with the ability of the formulation to control the release in the alkaline environments, of the gastrointestinal tract. To enhance the effect of the chitosan bead matrix, modern controlled release polymers was incorporated into the chitosan bead formulation. The effect of these polymers on drug release as well as on the morphology and strength of the chitosan beads was investigated and compared to granules with similar composition. <br><br> Ketoprofen was chosen as the model drug because of its physical and chemical properties. Ketoprofen is a non-steroidal anti-inflammatory drug with analgesic and antipyretic properties, commonly utilized in the treatment of severe rheumatoid arthritis. The short half-life of ketoprofen makes it an excellent candidate for formulation into the chitosan matrix bead formulation. By entrapping ketoprofen in chitosan beads, the production of a controlled release formulation with less gastric irritation could be achieved. <br><br> Beads were produced by dispersing ketoprofen in an aqueous acetic acid solution of chitosan. Varying concentrations of different types of controlled release polymers was added to the dispersion. The dispersion was dropped though a needle into a gently agitated solution of tripolyphosphate (TPP) and beads formed on contact with the TPP-solution. The beads were then separated, washed with deionised water, and freeze-dried. Matrix chitosan granules were produced by mixing of the dry ingredients, and wetting with a weak aqueous solution of acetic acid. The resulting mass was granulated through a 2 mm sieve and dried. These granules were further reduced in size by means of milling. Varying concentrations of controlled release polymers was also added to the granulate formulations prior to granulation. The concentrations of the polymers were added to render granules with the same polymer concentration as the beads. <br><br> On close investigation of the spherical beads by means of scanning electron microscopy the beads were found to have a porous surface structure with possible poor cross-linking. The inclusion of low concentrations 1% w/v of controlled release polymer appeared to enhance the surface structure but seemed to enhance the porosity of the internal structure. Granulate formulations appeared to have an irregular surface structure, which could have been a result of the milling process. The addition of controlled release polymers to the granules appeared to weaken the structure of the granules, as more surface cracks, and a flakier appearance was visible. Studies on the drug loading capacity showed that the addition of controlled release polymers to the bead formulations improved the drug loading capacity of the chitosan beads. The increase in drug loading was dependant on the type and concentration of polymer added, with Eudragit&reg; SI00 5% w/v having the most significant effect. The drug loading capacity of the granules remained constant throughout the study. <br><br> Friability testing revealed that beads produced by the inotropic gelation technique offered poor resistance to mechanical force. Once again the inclusion of certain controlled release polymers enhanced the resistance to mechanical force. This effect was also dependant on the type and concentration of polymer used, with Aqoat&reg; AS-HF weakening the beads, and Kollidon&reg; SR strengthening the beads resistance to friability. <br><br> Solubility and swelling tests revealed that bead formulations would be a much better option for obtaining controlled release, as granules showed a high degree of solubility and degradation. This is due to the fact that the cross-linking of chitosan with TPP significantly reduces the solubility of the beads. <br><br> Dissolution testing on formulations showed that some formulations succeeded in the initial objectives of the study. Kollidon&reg; SR formulations delayed drug release with almost the same effectiveness as chitosan beads in acidic environments, and also proved to act as controlled release formulations in the alkaline testing medium. Furthermore bead formulations all fared better at delaying and controlling the release of the model drug in both dissolution mediums. Although some formulations proved to be successful, it is speculated that the amounts of controlled release polymer used in the study might have been too high. Future studies conducted with less than 1% controlled release polymer, especially Kollidon&reg; SR may prove to be very rewarding. <br><br>