Development of additive manufactured solid dosage formulations containing orphan drug using quality by design (QBD) principles

"Orphan Drugs" are drugs for rare diseases, with a small market volume and high R&D expenditures. In this study, an oral tablet formulation was developed for rufinamide, which is one of the orphan drugs used in Lennox-Gastout syndrome, which needs to be produced in low scale. Rufinamide is an active substance from BCS Class II group with low water solubility. Due to its low solubility, it exhibits non-linear pharmacokinetics between 200 mg and 1200 mg doses, and therefore its therapeutic dose is very high (3200 mg). The aim of the study is to develop a formulation that will accelerate the dissolution behavior of rufinamide and provide the same effect at lower doses. Development studies were carried out with a risk analysis-based systematic approach in line with the principles of Quality by Design. The analytical method used in in-vitro dissolution analysis has been examined by statistical experimental design and a design space has been established. It was determined that the solid dispersion formed as a result of the melting of the formulation components during the filament extrusion applied in the FDM technique increased the dissolution, and the dissolution increased even more with the 3DP design. It was determined that the developed optimum formulation dissolved much higher than reference formulation at therapeutic dose (1600 mg). According to the MTT cytotoxicity studies carried out, it was observed that the highest cell viability could be achieved with the optimum 3DP tablet in both Hep G2 and Caco-2 cell lines. Additionally, it was observed that the highest Caco-2 permeability was obtained with the optimum 3DP formulation. Finally, the in-vivo pharmacokinetic behavior of the optimum 3DP tablet in the test and reference product was examined and it was seen that the AUC and Cmax values were higher in the Optimum 3DP tablet formulation compared to the reference product Inovelon® film tablet at a dose of 40 mg / kg. With the developed formulation in the thesis study, thanks to the increased solubility of the active substance, the 3DP tablet formulation, which provides an effective treatment with a lower dose compared to the commercial preparation, was developed, and this efficiency was proven in-vitro and in-vivo.