Objective: The inkjet printing (IP) and fused deposition modeling (FDM) technologies have emerged in the pharmaceutical field as novel and personalized formulation approaches. Specific manufacturing factors must be considered in each adopted methodology, i.e., the development of suitable substrates for IP and the incorporation of highly thermostable active pharmaceutical compounds (APIs) for FDM. In this study, IP and FDM printing technologies were investigated for the fabrication of hydroxypropyl methylcellulose-based mucoadhesive films for the buccal delivery of a thermolabile model drug. Significance: This proof-of-concept approach was expected to provide an alternative formulation methodology for personalized mucoadhesive buccal films. Methods: Mucoadhesive substrates were prepared by FDM and were subjected to sequential IP of an ibuprofen-loaded liquid ink. The interactions between these processes and the performance of the films were evaluated by various analytical and spectroscopic techniques, as well as by in vitro and ex vivo studies. Results: The model drug was efficiently deposited by sequential IP passes onto the FDM-printed substrates. Significant variations were revealed on the morphological, physicochemical and mechanical properties of the prepared films, and linked to the number of IP passes. The mechanism of drug release, the mucoadhesion and the permeation of the drug through the buccal epithelium were evaluated, in view of the extent of ink deposition onto the buccal films, as well as the distribution of the API. Conclusions: The presented methodology provided a proof-of-concept formulation approach for the development of personalized mucoadhesive films.

To this day, the oral delivery of biomacromolecules remains a major developmentally-oriented challenge. A combinatorial approach was followed at this study, to formulate an efficient carrier for the in vitro delivery of a model macromolecule, fluorescein isothiocyanate–dextran 4 kDa (FD4). The model macromolecule was formulated in a self-assembling peptide hydrogel (ac-(RADA)₄-CONH₂), prior to deposition in a hydroxypropyl methylcellulose-phthalate (HPMCP)-based 3D printed capsule. Loading of FD4 was investigated for potential alterations on the structural (AFM) and gelling properties of the peptide carrier. Thermal analysis and morphological properties of the 3D printed capsulea were assessed by TGA, DSC and microscopy studies. For the peptide hydrogel, similar release profiles of FD4 were recorded in simulated gastric fluid pH 1.2 and phosphate buffer saline pH 7.4, indicating the need for a structural barrier, to protect the peptide carrier from the acidic environment of the stomach. The pH responsive character of the HPMCP-based capsule was evidenced in the release profiles of FD4 in a sequence of release media, i.e. simulated gastric fluid pH 1.2, simulated intestinal fluid pH 6.8 and phosphate buffer saline pH 7.4. The results supported the combinatorial formulation approach as a promising system for the efficient oral delivery of biomacromolecules.

Fused deposition modelling (FDM) is the most extensively employed 3D-printing technique used in pharmaceutical applications, and offers fast and facile formulation development of personalized dosage forms. In the present study, mesoporous materials were incorporated into a thermoplastic filament produced via hot-melt extrusion and used to produce oral dosage forms via FDM. Mesoporous materials are known to be highly effective for the amorphization and stabilization of poorly soluble drugs, and were therefore studied in order to determine their ability to enhance the drug-release properties in 3D-printed tablets. Celecoxib was selected as the model poorly soluble drug, and was loaded into mesoporous silica (MCM-41) or mesoporous magnesium carbonate. In vitro drug release tests showed that the printed tablets produced up to 3.6 and 1.5 times higher drug concentrations, and up to 4.4 and 1.9 times higher release percentages, compared to the crystalline drug or the corresponding plain drug-loaded mesoporous materials, respectively. This novel approach utilizing drug-loaded mesoporous materials in a printed tablet via FDM shows great promise in achieving personalized oral dosage forms for poorly soluble drugs.

The potential of fused filament fabrication (FFF) for the administration of active pharmaceutical compounds is a recent approach to develop complex and custom-made drug delivery systems (DDSs). However, the FFF technology is characterized by certain limitations, which are associated with the nature of the process, i.e., the required mechanical properties of the feedstock, as well as the thermal stability of the incorporated polymers, excipients and active compounds. Thus, hybrid DDSs have been recently introduced, to overcome these boundaries. The concept of these systems is defined by the effective coupling of FFF with conventional manufacturing technologies, as a novel pathway to expand the available pool of raw materials and pharmaceutical applications of FFF.

Poorly soluble drugs represent a substantial portion of emerging drug candidates, posing significant challenges for pharmaceutical formulators. One promising method to enhance the drug's dissolution rate and, consequently, bioavailability involves transforming them into an amorphous state within mesoporous materials. These materials can then be seamlessly integrated into personalized drug formulations using Additive Manufacturing (AM) techniques, most commonly via Fused Deposition Modeling. Another innovative approach within the realm of AM for mesoporous material-based formulations is semi-solid extrusion (SSE). This study showcases the feasibility of a straightforward yet groundbreaking hybrid 3D printing system employing SSE to incorporate drug-loaded mesoporous magnesium carbonate (MMC) into two different drug formulations, each designed for distinct administration routes. MMC was loaded with the poorly water-soluble drug ibuprofen via a solvent evaporation method and mixed with PEG 400 as a binder and lubricant, facilitating subsequent SSE. The formulation is non-aqueous, unlike most pastes which are used for SSE, and thus is beneficial for the incorporation of poorly water-soluble drugs. The 3D printing process yielded tablets for oral administration and suppositories for rectal administration, which were then analyzed for their dissolution behavior in biorelevant media. These investigations revealed enhancements in the dissolution kinetics of the amorphous drug-loaded MMC formulations. Furthermore, an impressive drug loading of 15.3 % w/w of the total formulation was achieved, marking the highest reported loading for SSE formulations incorporating mesoporous materials to stabilize drugs in their amorphous state by a wide margin. This simple formulation containing PEG 400 also showed advantages over other aqueous formulations for SSE in that the formulations did not exhibit weight loss or changes in size or form during the curing process post-printing. These results underscore the substantial potential of this innovative hybrid 3D printing system for the development of drug dosage forms, particularly for improving the release profile of poorly water-soluble drugs.