Hybrid Drug Delivery Systems Made by Combining FFF 3D Printing & Conventional Manufacturing

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Over the last few years, research has shown that 3D printing has a lot of potential for fabricating drug delivery systems. Now, a group of researchers from the Aristotle University of Thessaloniki in Greece and the University of Copenhagen in Denmark have published a paper, “Manufacturing of hybrid drug delivery systems by utilizing the fused filament fabrication (FFF) technology,” outlining how combining FFF technology with conventional forms of manufacturing can create hybrid drug delivery systems. The paper explores the variety of techniques already used to achieve hybrid drug printing, as well as future possibilities, with the goal of expanding the materials and applications for FFF in pharmaceutical production.

The abstract states, “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 team explains that FFF 3D printing is great for creating complicated DDSs with specific properties, such as multilayered structures that offer tailored drug release.

“The commercial release of the first 3D-printed tablet (Spritam®, Aprecia Pharmaceuticals), together with the first reported application of FFF in pharmaceutical technology, stimulated the academic sector globally,” they wrote. “This development was further motivating the emergence of novel formulation approaches for drug delivery by using the FFF technology. Since then, a growing number of printable materials has been reported during the development of FFF-printed DDSs; however, it should be noted that this number is moderate compared to the available thermoplastic polymers, excipients, and APIs used in the development of pharmaceutical products via standard technologies (e.g., granulation, tableting, pelletization, coating).”

However, FFF does have some limitations in the pharmaceutical sector, such as thermal degradation, few materials that can be ingested orally, and lack of process scale-up. There are some existing hybrid systems, which you can see below, that can help users get past these boundaries.

“This hybrid proof-of-concept approach aims to resolve the shortcomings of the FFF process, resulting in the fabrication of DDSs with enhanced functional properties,” the researchers stated.

FFF 3D printing can be used to fabricate container-like shapes, and several different filling formulations can be used to fill a printed capsule. Both an automatic and a manual approach can be used to complete the filling procedure.

“The produced hybrid DDSs incorporate the advantages of both manufacturing facets. For instance, the manual-filling approach provides the potential to incorporate a thermolabile API in the DDS, avoiding the unnecessary thermal stress to the sensitive API throughout the HME and FFF processing of the primary material,” they explained. “At the same time, this approach provides the possibility to adjust and tightly regulate the targeted delivery and the release mechanism of the API. Floating systems have been developed by combining FFF and tablet compression, exhibiting controlled drug release [8–10].”

Illustration of the potential of 3D printing for engineering drug release. The rows are representative examples of (top to bottom): different tablet geometries, their respective plots of normalized tablet width, and experimental/theoretical data of drug release (blue/red dotted lines) corresponding to the different tablet shapes. Reprinted with permission from reference [19].

The researchers outline the wide variety of multicompartmental drug delivery devices so far created, ranging from those loaded with suppository dosage forms and self-nanoemulsifying DDSs to drug-loaded hot melt extrudates, and both capsule and tablet shapes could potentially be used to perform targeted drug delivery of hydrogels and alginate beads. A dual-extruder 3D printer can be modified by replacing a printhead with a syringe, which can achieve an automated filling process. A modular 3D printer, used for tissue applications in the past, was used to perform both the 3D printing of drug capsules and an injection head for filling them with drugs with unique release profiles.

One of the first hybrid DDSs to use 3D printing was combined with electrospinning (ES) in order to make drug-loaded scaffolds.

“The ES process generates fibers of various diameters, inexpensively, with their most crucial advantage being that they can mimic the extracellular matrix. In turn, FFF is utilized both for its rapid structure prototyping capabilities and the mechanical properties of the objects. Thus, a drug-loaded electrospun graft was shielded with a 3D-printed outer layer to improve the mechanical properties and structural integrity of the scaffold,” they explained.

FFF 3D printing has also been used with injection molding in order fabricate bilayer dual drug-containing tablets, where a small part of the tablet, containing a customizable and personalized dose of one drug, was 3D printed. This part was placed in a mold, which is where the larger tablet part, with a non-custom dose of a second medication, was made. The technology has also been paired with inkjet printing in order to create tablets with QR codes and data matrices for safety purposes.

“Additive manufacturing might have a key role to personalize the production for both clinical trials as well as final commercial scale,” the researchers wrote. “As thermal degradation at moderate temperatures represents a major issue for most biologics and even small molecules, the development of hybrid DDSs for the effective delivery of these molecules can be a logical solution. Compartmentalized hybrid DDSs allow for personalization of not only the dose of different compounds in the same dosage unit, but also customization of the release behavior for each incorporated drug.”

A conceptualized hybrid DDS with multiple chambers that provide immediate (blue), delayed (red), and sustained (green) release profiles of different APIs, as well as functional elements (white), like permeation enhancers, enzyme inhibitors, and pH regulators.

They concluded that combining FFF 3D printing with other conventional techniques to make hybrid DDSs has great potential for the pharmaceutical sector by combining the advantages of each while potentially reducing the limitations of both.

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