Modified release formulations manufactured by hot-melt extrusion




Maincent, Julien

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Hot-melt-extrusion has recently gained interest in pharmaceutical industrial manufacturing due to numerous advantages such as the possibility for continuous manufacturing, low cost of operation or the absence of organic solvents. Hot-melt-extrusion success lies also in its ability to manufacture amorphous solid dispersions, which has been adopted as a method of choice in the pharmaceutical industry to overcome poor drugs water-solubility. Sustained release amorphous solid dispersions are challenging to formulate due to the low extent of supersaturation, the gelation phenomenon around the matrix and recrystallization. Different polymeric carriers for hot-melt-extruded amorphous tablets were evaluated for their ability to provide sustained release. Hydrophilic carriers were able to sustain amorphous drug release in high solubility environment. In lower solubility conditions, drug was trapped in the tablet due to its inability to dissolve and diffuse in the gel layer. In these low solubility conditions, enteric polymers can be used to sustain drug release due to their erosion based release mechanism and the prevention of media penetration. The efficacy of an itraconazole amorphous solid dispersion containing HPMCAS and Vitamin E TPGS was evaluated against invasive fungal infection by Aspergillus fumigatus. This formulation was selected due to its previously demonstrated high bioavailability in rats. Mice infected by Aspergillus fumigatus were treated orally with the formulation, which led to highly variable pharmacokinetic parameters and low efficacy. These were attributed to mice gastro intestinal tract low pH, reduced fluid volumes and low efficacy of itraconazole in mice model. In guinea pigs, high tissue levels were measured with significant decrease in Aspergillus fumigatus fungal burden. Hot-melt-extrusion processing was utilized to manufacture monolithic tablets containing Tramadol HCl and Affinisol™ HPMC. The potential for the tablet to prevent abuse by physical and chemical manipulation was investigated and compared to directly compressed tablet of the same composition. It was demonstrated that hot-melt-extrusion of Affinisol™ HPMC provides high physical strength to the tablets, thus preventing crushing by manual methods. Milling the tablets in a high shear grinder for minutes was necessary to break the tablets. Chemical extraction from milled tablets was also decreased for hotmelt-extruded tablets due to their larger particle size


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