Development of new solid oral formulations produced by hot-melt extrusion coupled with fused deposition modeling 3D printing

Fused deposition modeling is a popular three-dimensional printing technology known for its environmental friendliness, design flexibility, and user-friendly operation. It operates by extruding a filament through a heated nozzle, which deposits successive layers of material, solidifying onto a build plate based on a computer-generated design. Recently, the interest in applying fused deposition modeling in the pharmaceutical sector has been increased. A manufacturing step, hot-melt extrusion, is involved for the production of drug-loaded filaments. This thesis aims to showcase the polyvalence and benefits of implementing fused deposition modeling in the pharmaceutical field to develop innovative oral solid dosage forms.
Firstly, the modification of the drug dissolution rate by 3D printing has been studied. Low aqueous solubility drugs belonging to the second class of the Biopharmaceutics Classification System were examined. Hot-melt extrusion coupled with fused deposition modeling were studied to create printed dosage forms containing amorphous drugs to increase their solubility and release rate. High-dose cylindrical forms with various infill densities were successfully developed containing one-year stable amorphous solid dispersions of the BCS II active substance, itraconazole. The drug dissolution rate in the amorphous state significantly improved compared to crystalline itraconazole. The dissolution rate relied on infill density and polymers composition, altering surface-to-volume ratio and component distribution, respectively. The optimal formulation had a dissolution profile in acidic medium similar to the marketed drug product in Belgium.
Secondly, 3D printing's interest in personalized medicine has been investigated. Healthcare now emphasizes patient-centered care and individualized therapies, especially for vulnerable groups like children. As an example, adrenal insufficiency treatment with hydrocortisone was selected. The few marketed oral hydrocortisone products lack suitability for various required doses. Moreover, compounding capsules often fail to meet mass and content uniformity standards. Hence, high-quality oral solid dosage forms with low hydrocortisone contents were developed. Using the same filament but varying printed shapes dimensions, forms containing different drug doses were achieved. Two designs were created: an immediate release pediatric friendly red mini-waffle shape and a sustained release torus shape. Despite the considerable challenge of low drug doses, both printed forms met European Pharmacopeia specifications for mass uniformity, content uniformity, friability, and hardness.
This thesis proves that 3D printing is highly promising to develop low-dose and high-dose oral solid dosage forms thanks to the modification of printed forms shapes and sizes. This technology could be implemented in hospital and community pharmacies to produce drug products of advanced quality providing access to individualized healthcare for patients.