By Ishwor Poudel, R Jayachandra Babu, Department of Drug Discovery and Development, Auburn University
Orodispersible films (ODFs) are attractive dosage forms for their ease of personalization based on patient needs. Such customization could be highly significant for rapid relief, drugs with a narrow therapeutic index, and patients with dysphagia. ODFs are portable and don't need water, making them patient-friendly. With recent advances, additive manufacturing (AM) offers the possibility of rapid fabrication and efficient dispensing through pharmacies, which could be considered a boon for small-scale manufacturing. Earlier research on 3D-printed ODFs was primarily based on first-generation technologies like FDM (Fused Deposition Modeling), which mainly utilized amorphization of drug and film porosity to improve dissolution rate (1). Then, multiple possibilities were explored using other extrusion techniques like RAM extrusion (2) for personalized films, semi-solid extrusion (SSE) for multilayered films with possibilities of multiple drug loading (3), and even precision control by using microdispensing drop-on-demand printing of ODFs using Inkjet Printing (IJP) (4).
After almost eight years of Spritam® approval, the streamlined utilization of 3D-Printing (3DP) in pharmaceutical manufacturing is still limited. The orodispersible tablets manufactured with Zipdose technology® showed promise of large-scale manufacturing of oral dosage forms using 3DP. Industrial production of personalized ODFs is complex, uncontrolled, and less efficient with conventional film-casting techniques and demands resource-intensive post-processing. 3DP could provide that cutting edge to streamline personalization ranging from small-scale pharmacy settings to large-scale industrial manufacturing. IJP and SSE-based printing have been extensively investigated; however, the ink formulation and compatibility/edibility of the excipients need to be evaluated for each case. The regulatory guidelines for conventional ODFs alone are not straightforward through official Pharmacopoeias, making the quality control parameters of 3D-Printed ODFs are further challenging. Non-destructive quality methods like Near-Infrared (NIR) and technologies transferable in the pharmacy setting or as in-line procedures during continuous manufacturing could open newer perspectives of dose tailoring based on patients (5).
ODF fabrication using various 3DP technologies for quick and customized fabrication is a practical method for making small batches of ODFs. These technologies allow the fabrication of patient-friendly medications and improve overall delivery properties. Various hydrophilic polymers and drugs are being investigated using printing parameter variations and techniques. This development could significantly optimize manufacturing ODFs, oromucosal formulations, and vaccines. ODFs also have a high chance of shifting their application potential towards other target regions like eyes, wound sites, nasal delivery, and skin cancer complexities. The concept of ODF-based vaccines has been rising during the COVID pandemic; an ODF film-based vaccine delivering the influenza virus vaccine has been forwarded as an injection alternative (6). In addition, ODFs are dynamic in offering the advantage of personalized pharmacotherapy based on the nature of patients, drugs, and related doses through changes in printed dimensions. Small-scale fabrication in pharmacy setting as an extemporaneous dosage form for dispensing could be achieved within no time. The acceptability, palatability, and swallowability of ODFs are investigated through randomized controlled trials to establish ODFs as the preferred formulation for neonates and infants (7). The multilayered ODFs could decrease the pill burden through the concept of polypharmacy, which could be a boon for geriatric patients with dysphagia and active multi-drug regimens. However, limited thickness could always result in low drug loading; thus, drugs with low dose requirements could be the ideal candidates for ODF.
Inkjet printing is considered 2-dimensional as continuous jet printing or drop-on-demand printing, usually drop dispensing controlled under the response of trigger signal, either piezoelectric or thermal. The printing could be translatable to large scale by adding multiple printheads; however, judicious use of feed solvent and optimal nozzle size becomes a prerequisite. Extrusion-based techniques, along with SSE, are getting popular for ODF fabrication but depend heavily on the properties of feed materials and printing parameters to achieve precision and uniformity. The integrity of the whole printing process and stability of the final structure depends on the balance and optimization of printing parameters, which could be time-intensive during development on a case-to-case basis. Essential parameters like temperature control before and during extrusion and its impact on printing have not been investigated in detail in the available literature. Its impact on the rheology of the mix could make or break the whole printing process. Other important printing parameters are the printhead movement, printing speed, and extrusion rate, which ensure the replication of the desired CAD model. With multiple printing parameters and printheads involved in the fabrication process for large-scale manufacturing, there are many challenges to building a final structure with the desired consistency and precise loading. Currently, newer technologies like Machine Learning (ML) and AI (Artificial Intelligence) could aid the overall efficiency of the 3DP fabrication process, mainly with process optimization and excipient selection.
Based on ESPACENET (https://worldwide.espacenet.com/), a free online database(8) offered by the European Patent Office (EPO), just six patents on 3D Printed ODFs were available when keywords”3D-Printing” and “Orodispersible” was used for the search (Table 1), making the insufficient research in this area evident. The compounded annual growth rate (CAGR) for the global market of ODFs has increased by 10.5% from 2018 to 2023(9), while Transparency Market Research (TMR) estimated the global market of ODF to reach 15.9 billion by 2024. These statistics reflect the true future market potential of ODFs, and with the growth of 3DP technologies, the future appears brighter. With advancements in the second generation of 3DP technologies, the evolution of AI, and the shift of treatment regimens towards personalized therapy, ODFs could be integral dosage forms that could incorporate all three aspects together. The challenges to incorporating 3DP in manufacturing are evident. However, it is inevitable that the countless possibilities towards small scale manufacturing and personalized regimen outweigh the current limitations by a wider margin.
Table I. List of patents filed on 3D-Printed Orodispersible Films obtained from the database of European Patent Office(worldwide.espacenet.com) with keywords ‘3D-Printed’ and ‘Orodispersible’.
References
1. Jamróz, Witold, et al. "3D printed orodispersible films with Aripiprazole." International journal of pharmaceutics 533.2 (2017): 413-420.
2. Musazzi, Umberto M., et al. "Personalized orodispersible films by hot melt ram extrusion 3D printing." International journal of pharmaceutics 551.1-2 (2018): 52-59.
3. Elbl, Jan, Jan Gajdziok, and Jan Kolarczyk. "3D printing of multilayered orodispersible films with in-process drying." International Journal of Pharmaceutics 575 (2020): 118883.
4. Tam, Chak Hin, et al. "Drop-on-demand printing of personalised orodispersible films fabricated by precision micro-dispensing." International Journal of Pharmaceutics 610 (2021): 121279.
5. Musazzi, Umberto M., et al. "Trends in the production methods of orodispersible films." International journal of pharmaceutics 576 (2020): 118963.
6. Tian, Yu, et al. "Development of an orodispersible film containing stabilized influenza vaccine." Pharmaceutics 12.3 (2020): 245.
7. Klingmann, Viviane, et al. "Acceptability of an orodispersible film compared to syrup in neonates and infants: A randomized controlled trial." European Journal of Pharmaceutics and Biopharmaceutics 151 (2020): 239-245.
8. Worldwide.espacenet.com: Free patent database by European Patent Office (Accessed on 05/01/2024)
9. Gupta, Maram Suresh, et al. "Printing methods in the production of orodispersible films." AAPS PharmSciTech 22 (2021): 1-17.