How do infill density and polymer composition of 3D printed solid oral forms impact the dissolution profile of a BSCII drug ?

Introduction: In recent years, scientific interest in the use of three-dimensional (3D) printing for drug manufacturing has considerably increased in the pharmaceutical field. Modifying the drug release profile by varying the printing parameters of printed forms is one reason why Fused Deposition Modelling (FDM) appears to be a promising tool[1]. In fact, many active pharmaceutical ingredients (API) are classified in the Biopharmaceutics Classification System class II (BCSII) since they are poorly water soluble[2]. Therefore, elaboration of new solid oral forms by hot-melt extrusion (HME) coupled with FDM is a strategy to enhance the dissolution rate of BCSII API by the formation of amorphous solid dispersions (ASD) of these drugs in polymers and the elaboration of printed forms with complex geometries.
Materials and methods: Itraconazole (ITZ) was chosen as the model BCSII drug. HME was
performed on three formulations containing 25% of ITZ and the following proportions of
Affinisol® 15LV (hydroxypropylmethylcellulose) and Kollidon® VA 64 (vinylpyrrolidone-vinyl
acetate copolymer): 100/0, 70/30 and 40/60. For each formulation, printed forms with infill
densities of 20%, 50% and 80% and a constant weight were printed by FDM (Figure 1).
Results and discussion: Differential scanning calorimetry (DSC) analysis shows that ITZ is
completely amorphous in all the printed forms. Moreover, drug dosages show that no
degradation of ITZ has occurred during the production process. During the nine months of
storage of the printed forms, ITZ remained completely amorphous and no degradation
occurred. Results of dissolution tests in 0.1 M HCl indicate that the drug release rate is
improved in all the printed forms compared to ITZ in a crystalline form. For all the formulations, the lower the infill density of the printed form is, the faster the drug dissolution rate is. This phenomenon can be correlated with the surface/volume ratio of printed forms, measured by CT-scan. In addition, Fourier Transform Infrared (FTIR) Microscopy and Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) were used to analyse the distribution of the components within the printed forms. Results show that ITZ is distributed differentially within the two polymers depending on the ratio of both polymers in the formulations, influencing the dissolution profile of the drug.
Conclusion: Thanks to the association of Affinisol® 15LV and Kollidon®VA64 with ITZ, solid
oral forms with different infill densities were successfully printed and the drug release rate was improved. Both polymer composition and infill density of printed forms influence the dissolution rate of the BCSII drug they contain. The printed forms from the formulation 2 with an infill density of 20% even have a solubility profile similar to that of Sporanox® which is highly encouraging for future experiments. Through this study, we have demonstrated that the FDM technique allows the formation of stable ASD with a complex geometry leading to a
conventional oral solid dosage form. This technology is currently use to confirm these findings with other BCSII molecules.