(T0930-03-17) Fabrication of Caffeine Transdermal Film Using the Hot-Melt Extrusion and Fused Deposition Modeling 3D Printing

Purpose: Transdermal films are commonly made using solvent casting/evaporation methods with organic or aqueous solvents, which require extensive processing and drying times, resulting in increased costs, longer production times, and potential harm to drug stability. However, Fused Deposition Modeling (FDM) 3D printing and Hot-Melt Extrusion (HME) technology can offer solvent-free production, continuous processing, and dose flexibility, leading to more efficient and shorter processing times. In this study, HME and FDM 3D printing were used to create transdermal films, with caffeine as a model drug, to investigate the effects of insoluble polymers, caffeine and excipient content, and film thickness on drug release. The resulting films were non-adhesive but became bio-adhesive when applied to wet skin.

Methods: As seen in Table 1, various films containing different insoluble polymers (Ethyl Cellulose N22, Kollidon® SR, and Eudragit® RS PO) were fabricated using Polyethylene oxide (Polyox™ WSR N80) as a main matrix. The influence of each of these insoluble polymers on caffeine release rate was studied, fixing the film thickness at 500 μm and drug loading at 10% (w/w) (F1~F6). Among the insoluble polymers, Eudragit® RS PO was selected to constitute the films and studied further to identify which factor (Eudragit® RS PO content, drug content, film thickness) significantly influenced on caffeine release rate (F5~F12) utilizing the two-level full factorial design. An 11mm twin-screw extruder (Thermo Fisher Scientific, MA, USA) was used to fabricate drug-loaded filaments for the 3D printing of films. A 15 mm x 15 mm square with two different thicknesses (500μm, 700μm) was designed using Tinkercad software (Autodesk Tinkercad, Autodesk Inc., CA, USA) and was printed using a commercial FDM 3D printer (Prusa i3 MK3 3D desktop printer, Prusa Research, Prague, Czech Republic). An in-vitro drug release study of the films was conducted using USP apparatus 5, paddle over disk method. The mechanical properties of the films were measured using a texture analyzer.

Results: Adding 20% (w/w) of Ethyl Cellulose (EC) slightly decreased the initial drug release rate. It was expected that by increasing EC content from 20% (w/w) to 40% (w/w), the drug release rate would be decreased due to the increased insoluble component. However, the drug release rate was slightly increased with increased EC content. Kollidon® SR and Eudragit® RS PO showed similar drug release profiles at both 20% (w/w) (f2=84.20) and 40% (w/w) (f2=86.43) loading. When the content of Kollidon® SR and Eudragit® RS PO increased from 20% (w/w) to 40% (w/w), although the initial drug release rate was not much decreased, the terminal drug release rate was slightly decreased. As for the effect of caffeine content, Eudragit^® RS PO content, and film thickness on caffeine release, drug content did not significantly affect the drug release rate, but Eudragit^® RS PO content and film thickness significantly influenced on drug release rate. Among the films, the films made with 20% (w/w) Eudragit^®RS PO and 10% (w/w) caffeine (F5) showed the highest robustness. IncreasingEudragit^® RS PO and EC content decreased the burst strength and toughness of the films. However, Kollidon^® SR films showed a slight increase in those parameters and the highest extensibility. Increasing the film thickness (500 um to 700 um) increased burst strength and stiffness. However, an increase in caffeine loading decreased the burst strength, stiffness, and toughness of the films.

Conclusion: Caffeine-loaded transdermal films were developed using HME and FDM 3D printing. For controlling caffeine release, RS PO content and film thickness had a significant effect. Thus, it is expected that personalized and effective caffeine delivery may be achieved by modifying these parameters for the patients.

Formulation compositions

In-vitro release profiles of the films

Mechanical properties of the films