Development of a multiple-unit sustained release dosage form containing gliclazide
Multiple-unit drug delivery systems (MUDS) are oral dosage forms consisting of beads or pellets (either coated or uncoated) that may be compressed into tablets or encapsulated. Tablets consisting of beads have been well-defined in scientific literature as exhibiting the ability to deliver a dosage form capable of depicting a modified drug release profile. The purpose of this study was to ascertain whether such a tablet formulation (comprising beads) is capable of producing a dosage from displaying a sustained drug release profile. The selected fillers (CombiLac®, MicroceLac®, RetaLac®, Pharmacel® 101 and a 80:20 mixture of Cassava starch and Hydroxypropyl Methylcellulose) tested either as a powder or as a bead formulation (as well as with and without 10% w/w gliclazide), were subjected to analysis utilising the SeDeM Diagram Expert System to determine their suitability for direct compression. This investigation included a review of the powder's physical properties, dimensions, compressibility and lubricity. Through this model it can easily be observed which properties of the excipient are suitable for direct compression and where improvement may be recommended. Bead formulations were subsequently manufactured by means of extrusion-spheronisation utilising selected fillers and 10% w/w gliclazide. These combinations were studied using a full factorial design to identify the optimal concentration of lubricant (magnesium stearate) and binder (Kollidon® 90F) to be included in the final tablet formulations. Powder mixtures and beads were directly compressed into 9 mm concave tablets with a Korsch® single tablet press. The physical properties of the beads, powder tablets as well as bead tablets were studied and compared. Each tablet was formulated to weigh approximately 300 mg and contain 30mg gliclazide. Results showed that certain combinations of the binder and lubricant concentrations amounted to formulations displaying more appropriate physical properties to not only obtain acceptable tablets, but that may probably be able to aid in modified drug release. Generally, it could be concluded that the inclusion of magnesium stearate is necessary. Although the concentration was deemed less important through evaluation of most of the tablet properties, according to the disintegration analysis, a 1% w/w concentration will suffice. According to the full factorial design, the inclusion of a binder did not play a significant role, but the inclusion of Kollidon® 90F rendered diverse results where the exclusion of the binder favourably improved mass variation results; the 2% w/w concentration produced tablet formulations that exhibited harder and more resilient tablets; and formulations comprising 5% w/w Kollidon® 90F delivered tablets which depicted delayed disintegration properties. Furthermore, the type of filler included exerted some effect on tablet properties, though the method of production was of more importance. Powder formulations generally displayed more favourable tablet properties, except for the disintegration characteristic where the bead formulations were considered more ideal. Permitting these results obtained, formulations comprising 1% w/w magnesium stearate and 2% w/w Kollidon® 90F were selected for additional investigations. Following evaluation of the physical properties of the various tablet formulations; the formulations that were deemed optimal, through analysis by means of the full factorial design, were tested with regards to swelling, erosion and drug release properties. Drug release profiles were consequently compiled of the formulations (powder tablets, beads and bead tablets) that contained the different selected fillers. Overall, the various methods of manufacture each presented formulations that did not perform optimally. The powder tablet formulations generally exhibited faster drug release profiles where more gliclazide was obtained in solution (i.e. 100% released). Bead and bead tablet formulations, mostly depicted modified release profiles (either delayed release or slow release), but none of the formulations demonstrated a distinct sustained release profile. None of these formulations were able to release gliclazide completely, however, the RetaLac® bead tablet formulation depicted the most appropriate modified release profile.
- Health Sciences