Digital light processing (DLP) 3D printing technique applied in the fabrication of two-layered tablets: the concept of a combined polypill

Ivana Adamov; Djordje Medarević; Branka Ivković; Aleksandar Ivković; Svetlana Ibrić

doi:10.5937/arhfarm72-40365

Ivana Adamov University of Belgrade – Faculty of Pharmacy, Department of Pharmaceutical Technology and Cosmetology https://orcid.org/0000-0003-0918-323X
Djordje Medarević University of Belgrade – Faculty of Pharmacy, Department of Pharmaceutical Technology and Cosmetology
Branka Ivković University of Belgrade – Faculty of Pharmacy, Department of Pharmaceutical Chemistry
Aleksandar Ivković Academy of Applied Technical Studies
Svetlana Ibrić University of Belgrade – Faculty of Pharmacy, Department of Pharmaceutical Technology and Cosmetology

DOI: https://doi.org/10.5937/arhfarm72-40365

Keywords: DLP technique, hydrochlorothiazide, warfarin sodium, combined two-layered 3D tablets, personalized medicine

Abstract

Ever since 3D printing was introduced to the field of pharmacy, it has caused a paradigm shift from the manufacturing of large-scale to small batches of medicines tailored accordingly to the specific needs of patients. This study aimed to formulate and fabricate two-layered 3D tablets using the digital light processing (DLP) technique. Hydrochlorothiazide (HHT,5%,w/w) and warfarin sodium (WS,5%,w/w) were selected as model drugs. The printing process was initiated with 0.1% of photoinitiator, at a constant ratio of poly(ethylene glycol)diacrylate and poly(ethylene glycol) 400, 1:1, with the addition of water (10%,w/w). Single-layered tablets of 8.00 mm diameter and 1.50 mm thickness, containing HHT and WS respectively, were successfully printed, as well as combined two-layered 3D tablets, with each of the active substances in separate layers. Dissolution tests of single-layered tablets showed immediate, but incomplete release of WS (81.47±1.47%, after 45min), and prolonged and complete release of HHT (98.17±3.11%, after 8h), while significantly slower and incomplete release of both drugs from the combined two-layered 3D tablets was observed. The absence of drug-polymer interaction and presence of a layered cross-sectional tablet structure were confirmed. DLP technique enables simple and rapid fabrication of combined two-layered 3D tablets, while further optimization of formulation factors is necessary to achieve complete drug release.

References

1. Awad A, Fina F, Trenfield SJ, Patel P, Goyanes A, Gaisford S, et al. 3D printed pellets (Miniprintlets): A novel, multi-drug, controlled release platform technology. Pharmaceutics. 2019;11(4):148. doi: 10.3390/pharmaceutics11040148.

2. Rodríguez-Pombo L, Xu X, Seijo-Rabina A, Ong JJ, Alvarez-Lorenzo C, Rial C, et al. Volumetric 3D printing for rapid production of medicines. Addit Manuf. 2022;52:102673. doi: 10.1016/j.addma.2022.102673.

3. Trenfield SJ, Awad A, Goyanes A, Gaisford S, Basit AW. 3D Printing Pharmaceuticals: Drug Development to Frontline Care. Trends Pharmacol Sci. 2018;39(5):440–451. doi: 10.1016/j.tips.2018.02.006.

4. Vaz VM, Kumar L. 3D Printing as a Promising Tool in Personalized Medicine. AAPS PharmSciTech. 2021;22(1). doi: 10.1208/s12249-020-01905-8.

5. Alexander AE, Wake N, Chepelev L, Brantner P, Ryan J, Wang KC. A guideline for 3D printing terminology in biomedical research utilizing ISO/ASTM standards. 3D Print Med. 2021;7(8). doi: 10.1186/s41205-021-00098-5.

6. Wang J, Goyanes A, Gaisford S, Basit AW. Stereolithographic (SLA) 3D printing of oral modified-release dosage forms. Int J Pharm. 2016;503(1–2):207–212. doi: 10.1016/j.ijpharm.2016.03.016.

7. Patel DK, Sakhaei AH, Layani M, Zhang B, Ge Q, Magdassi S. Highly Stretchable and UV Curable Elastomers for Digital Light Processing Based 3D Printing. Adv Mater. 2017; 29(15). doi: 10.1002/adma.201606000.

8. Stanojević G, Medarević D, Adamov I, Pešić N, Kovačević J, Ibrić S. Tailoring Atomoxetine Release Rate from DLP 3D-Printed Tablets Using Artificial Neural Networks: Influence of Tablet Thickness and Drug Loading. Molecules. 2020;26(1):111. doi: 10.3390/molecules26010111.

9. Xu X, Robles-Martinez P, Madla CM, Joubert F, Goyanes A, Basit AW, et al. Stereolithography (SLA) 3D printing of an antihypertensive polyprintlet: Case study of an unexpected photopolymer-drug reaction. Addit Manuf. 2020;33:101071. doi: 10.1016/j.addma.2020.101071.

10. Kadry H, Wadnap S, Xu C, Ahsan F. Digital light processing (DLP) 3D-printing technology and photoreactive polymers in fabrication of modified-release tablets. Eur J Pharm Sci. 2019;135:60–67. doi: 10.1016/j.ejps.2019.05.008.

11. Adamov I, Stanojević G, Medarević D, Ivković B, Kočović D, Mirković D, et al. Formulation and characterization of immediate-release oral dosage forms with zolpidem tartrate fabricated by digital light processing (DLP) 3D printing technique. 2022;624:122046. doi: 10.1016/j.ijpharm.2022.122046.

12. Krkobabić M, Medarević D, Cvijić S, Grujić B, Ibrić S. Hydrophilic excipients in digital light processing (DLP) printing of sustained release tablets: Impact on internal structure and drug dissolution rate. Int J Pharm. 2019;572:118790. doi: 10.1016/j.ijpharm.2019.118790.

13. Wang J, Zhang Y, Aghda NH, Pillai AR, Thakkar R, Nokhodchi A, et al. Emerging 3D printing technologies for drug delivery devices: Current status and future perspective. Adv Drug Deliv Rev. 2021;174:294–316. doi: 10.1016/j.addr.2021.04.019.

14. Robles-Martinez P, Xu X, Trenfield SJ, Awad A, Goyanes A, Telford R, et al. 3D printing of a multi-layered polypill containing six drugs using a novel stereolithographic method. Pharmaceutics. 2019;11(6):274. doi: 10.3390/pharmaceutics11060274.

15. Jie Y, Tan N, Pong W, Singh J, Khanolkar J, Yao X. On-demand fully customizable drug tablets via 3D printing technology for personalized medicine. J Control Release. 2020;322:42–52. doi: 10.1016/j.jconrel.2020.02.046.

16. Goh O, Goh WJ, Lim SH, Hoo GS, Liew R, Ng TM. Preferences of Healthcare Professionals on 3D-Printed Tablets: A Pilot Study. Pharmaceutics. 2022;14(7):1521. doi: 10.3390/pharmaceutics14071521.

17. Alayoubi A, Zidan A, Asfari S, Ashraf M, Sau L, Kopcha M. Mechanistic understanding of the performance of personalized 3D-printed cardiovascular polypills: A case study of patient-centered therapy. Int J Pharm. 2022;617:121599. doi: 10.1016/j.ijpharm.2022.121599.

18. Pereira BC, Isreb A, Isreb M, Forbes RT, Oga EF, Alhnan MA. Additive Manufacturing of a Point-of-Care “Polypill:” Fabrication of Concept Capsules of Complex Geometry with Bespoke Release against Cardiovascular Disease. Adv Healthc Mater. 2020;9(13). doi: 10.1002/adhm.202000236.

19. Edwards HD, Webb RD, Conway SE. Effect of oral diuretics on chronic warfarin therapy: A retrospective study. Expert Opin Drug Saf. 2012;11(3):375–380. doi: 10.1517/14740338.2012.624091.

20. Krkobabić M, Medarević D, Pešić N, Vasiljević D, Ivković B, Ibrić S. Digital light processing (DLP) 3D printing of atomoxetine hydrochloride tablets using photoreactive suspensions. Pharmaceutics. 2020;12(9):833. doi: 10.3390/pharmaceutics12090833.

21. Khan A, Iqbal Z, Shah Y, Ahmad L, Ullah Z, Ullah A. Enhancement of dissolution rate of class II drugs (Hydrochlorothiazide); a comparative study of the two novel approaches; solid dispersion and liqui-solid techniques. Saudi Pharm J. 2015;23(6):650–657. doi: 10.1016/j.jsps.2015.01.025.

22. Anderson ME, Delmarre D, Gao D, El-Khateeb MA, Centeno C-JS, Pathak SR, inventors; Morton Grove Pharmaceuticals, Inc., assignee. Stable warfarin sodium liquid formulation and method of making same. World patent WO 2006/138534 A2. 2006 December 28.

23. de Souza CMP, dos Santos JAB, do Nascimento AL, Chaves Júnior JV, de Lima Ramos Júnior FJ, de Lima Neto SA, et al. Thermal analysis study of solid dispersions hydrochlorothiazide. J Therm Anal Calorim. 2018;131(1):681–689. doi: 10.1007/s10973-017-6091-0.

24. Dimitrokalli E, Fertaki S, Lykouras M, Kokkinos P, Orkoula M, Kontoyannis C. Warfarin Sodium Stability in Oral Formulations. Molecules. 2021;26(21):6631. doi: 10.3390/molecules26216631.

25. Banerjee A, Blasiak B, Pasquier E, Tomanek B, Trudel S. Synthesis, characterization, and evaluation of PEGylated first-row transition metal ferrite nanoparticles as: T 2 contrast agents for high-field MRI. RSC Adv. 2017;7(61):38125–38134. doi: 10.1039/C7RA05495E.

26. Clark EA, Alexander MR, Irvine DJ, Roberts CJ, Wallace MJ, Sharpe S, et al. 3D printing of tablets using inkjet with UV photoinitiation. Int J Pharm. 2017;529(1–2):523–530. doi: 10.1016/j.ijpharm.2017.06.085.

27. Leopold LF, Ruginǎ D, Oprea I, Diaconeasa Z, Leopold N, Suciu M, et al. Warfarin-capped gold nanoparticles: Synthesis, cytotoxicity, and cellular uptake. Molecules. 2019;24(22):4145. doi: 10.3390/molecules24224145.