ADDITIVE MANUFACTURING IN PHARMACEUTICAL FORMULATION - DEVELOPMENT OF BIODEGRADABLE PRINTED DOSAGE FORMS FOR ORAL DRUG DELIVERY

摘要

The main focus of pharmaceutical research and development in recent decades has gradually shifted from synthesis of new drug molecules towards personalized (precision) medicine, where the drug dosage and release rate are tailored in order to fit the needs of each specific patient. Together with new discoveries in diagnostics and pharmacogenomics, this has led to increased need for novel formulation methods, which would enable to dynamically adjust the characteristics of each produced dosage form (such as tablet, pill, capsule, etc.). Amongst the most promising techniques is 3D printing of tablets or films, a subject of a rising number of published articles, especially after the FDA approval of the first printed tablet, Spritam. The Fused Deposition Modelling (FDM) technique is most frequently cited, since it's commercially available and offers the possibility to produce biodegradable dosage forms with defined drug contents and complex inner structures (affecting the drug's release rate), potentially also containing multiple drugs with varying release profiles. The first step of this technique is the conversion of the drug and chosen additives (FDA approved "excipients") into solid filaments, used as feed material for the printer. To be able to print pharmaceutically relevant tablets, the components had to meet certain criteria - chemical and thermal stability of the drug during the process and storage, excipient biodegradability, drug content homogeneity, the dissolution rate had to be in a desired range, etc. In addition, the filaments had to exhibit suitable mechanical properties in order to enable reproducible printing with good resolution. Several types of additives were employed -fillers, plasticizers, glidants, desiccants and disintegrants. To determine the specific effect of the composition on the relevant properties of the filaments, mechanical stability, dynamic viscosity and composition homogeneity were analyzed and the observed trends were used to determine the ideal filament composition. Furthermore, the crystalline/amorphous structure of the drugs after the extrusion was analyzed (using X-ray diffraction and differential scanning calorimetry) and the dissolution kinetics of the tablets was measured using chromatography and UV spectroscopy. After the optimizations, tablets were produced successfully (example shown in Fig. 1). Analogically, gels for the production of fast-dissolving oro-dispersible films were prepared and printed using syringe extrusion printing. To determine, how to adjust the structures of printed dosage forms to achieve desired dissolution profiles, mathematical simulation was employed, as described in the presentation of Z. Grof ("Evolutionary algorithm for the design of 3D-printed tablets").