oa Oral formulations of metformin in semi-solid matrices using solvent evaporation method: Characterization and in vitro dissolution testing

Purpose. To formulate and evaluate sustained-release hard gelatin capsules (HGC) filled with Metformin hydrochloride (MH) dispersed in semisolid matrices able to increase MH bioavailability and address the shortcomings in the currently marketed sustained-release tablets. Methods. Gelucire® 50/13 and various proportions of high molecular weight hydrophilic polymers, hydrophobic oily semisolid excipients, and muco-adhesive polymeric materials were dissolved in dichloromethane (DCM). MH powder previously micronized (250 micron) was suspended in the excipients' prepared solution. DCM was evaporated in the fume hood for 12 hours at room temperature followed by four hours of evaporation under vacuum at 40°C using vacuum oven. The prepared MH loaded matrices were filled in HGC each containing 500 mg MH and were subsequently characterized using Differential Scanning Calorimetry (DSC) and X-Ray Diffraction Analysis (XRD). The prepared HGC were subjected to content uniformity and in vitro dissolution testing according to the USP-35 compendial requirements. The dissolution data were compared to instant and sustained-release marketed tablets. Results. MH content in HGC ranged from 98 to 101%. All the prepared semisolid filled HGC resulted in extended-release profiles of MH that lasted between 3 to 7 hours and demonstrated a release pattern which typically follows the release from mixes of triglycerides with polyethylene glycol esters of fatty acids. The incorporation of muco-adhesive excipients like Carbomer to the Gelucire® 50/13-MH semisolid matrices extended the release of MH from 3 hours initially to 7 hours due to the formation of a gel layer around the matrix. However, the incorporation of excipients like PEG35000 and Gelucire® 44/14 along with the muco-adhesive excipients sustained the release of MH up to 9 hours. XRD analysis of the MH prepared matrices demonstrated minor changes in the crystalline nature of MH. Depending on the loading ratios and the nature of the semisolid matrices used, DSC analysis revealed the changes in MH crystallinity to be from 100 to 17%. Conclusion. HGC formulated using semisolid matrices showed promising results in extending the release of MH. However, bioavailability studies to test the ability of such Gelucire based HGC of MH to improve its bioavailability and in vivo residence times are future plans. Acknowledgements: This work was made possible by a NPRP award [NPRP 09-795-3-215] to HM Younes from the Qatar National Research Fund (a member of The Qatar Foundation). The statements made herein are solely the responsibility of the authors.