Formulation of a multiple-unit pellet solid oral delivery system for metformin and gliclazide
Abstract
Non-compliance is one of the contributing factors leading to poor treatment response in patients with chronic conditions such as diabetes mellitus (DM), due to the complex regimens often used in the management of these conditions. Fixed-dose combinations (FDCs) simplify medication regimens where different medicines are needed for the treatment of a single disease. The preparation of multiple-unit pellet system (MUPS) dosage forms allow the incorporation of different incompatible drugs in one dosage form and the minimisation of side-effects and the possibility to improve patient compliance amongst other benefits. In this study, a FDC MUPS capsule containing metformin and gliclazide was developed. A factorial design was used to formulate different bead formulations differing with respect to filler, binder and disintegrant. The amount of the active ingredients (metformin and gliclazide) used in the preparation of beads was varied between 5 and 10% w/w. The fillers used were Pharmacel® (microcrystalline cellulose (MCC) and MicroceLac® (MCC-lactose)). The disintegrant used was Ac-di-sol® (super-disintegrant) at a concentration level of either 0.5 or 1% w/w. Kollidon® VA 64 was used as binder at either a 3 or 5% w/w concentration level. The bead formulations were characterised with respect to flow rate, critical orifice diameter (COD), Hausner's ratio and % compressibility. After flowability characterisation, the bead formulations were assayed (for metformin and gliclazide content) and formulations with an assay value of ? 90% (for both active ingredients) were selected and filled into hard gelatin capsules to render FDC dosage forms for metformin-gliclazide. These capsule formulations were evaluated with respect to mass variation, disintegration time and dissolution behaviour. The flowability results indicated that all the bead formulations exhibited good to excellent flow. All capsule formulations complied with the specifications as set by the British Pharmacopoeia (BP) regarding mass variation and disintegration time. All the formulations exhibited average percentage dissolution values of 92.43 — 101.12% and 87.18 — 97.91% after 360 min for metformin and gliclazide, respectively. A marked slower and erratic initial dissolution rate for gliclazide, regardless of the filler (Pharmacel® orMicroceLac®) or excipients used, was observed. All the capsule formulations exhibited more than 80% dissolution for metformin within 30 min from the start of the dissolution study. Metformin therefore exhibited a higher and faster dissolution rate compared to gliclazide. The extent of metformin and gliclazide dissolution (AUC(0-360)) for both metformin and gliclazide were similar in all the formulations with no statistically significant differences (ANOVA, p ? 0.05). Results from this study indicated that the excipients used in this study had no pronounced influence on the physical capsule properties as well as the release of the active ingredients from the dosage form. However, the marked slower and erratic dissolution behaviour of gliclazide in comparison to metformin as noted in this study, may in all likelihood be attributed to the difference in solubility between these two drugs It is evident from this study that a MUPS FDC capsule dosage form containing metformin and gliclazide that is able to render both drugs pharmaceutically available in solution, could be prepared successfully, although a higher drug load of one or both drugs should be considered in a future study.
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- Health Sciences [2060]