ÇOKLU İLAÇ YÜKLÜ 3D BASKILI DOZAJ FORMLARINA ODAKLANAN 3D BASKI TEKNOLOJİLERİNE GENEL BAKIŞ

Abstract

Amaç: Bu derleme, 2015 yılında onaylanan ilk üç boyutlu baskılı dozaj formu olan Spritam®’dan bu yana, üç boyutlu baskılama (3DP) teknolojileriyle üretilen çoklu ilaç yüklü dozaj formlarına odaklanmaktadır. Sonuç ve Tartışma: 3DP sayesinde, tek bir dozaj formunda birden fazla ilacın entegrasyonu mümkün hale gelmiş olup, bu durum dozaj, ilaç salım profilleri ve geometrik yapılar açısından önemli bir tasarım esnekliği sağlamaktadır. Bu formülasyonlar, farklı ilaçları tek bir ünitede birleştirerek önemli bir tasarım esnekliği sunar ve özellikle birden fazla ilaç kullanımını gerektiren hastalıklar için tedavi stratejilerini optimize etme potansiyeline sahiptir. Geniş literatür araştırması, çok bölmeli kapsüller veya tabletler, farklı salım kinetiği gösteren çift katmanlı veya çok katmanlı tabletler ve çekirdek/kabuk yapılı tabletler gibi çeşitli geometrilere sahip 3D baskılı dozaj formları elde etmek için en yaygın kullanılan yöntemin Eriyik Birikim Modelleme (FDM) olduğunu ortaya koymaktadır. Çoklu ilaç yüklü 3D baskılı dozaj formları, sabit doz kombinasyonlarını kişiselleştirme noktasında önemli bir potansiyel sunmaktadır ve kişiselleştirilmiş tıbbın ilerletilmesinde ve polifarmasiye bağlı terapötik sonuçların iyileştirilmesinde umut vadeden bir araç olarak değerlendirilmektedir. Bu yenilikçi yaklaşım, terapötik etkinliği artırabilir, yan etki riskini azaltabilir ve hasta uyumunu iyileştirebilir. Mevcut araştırmaların ilerlemesiyle birlikte, bu formülasyonlar ilaç geliştirme ve tedavi stratejilerinin geleceği açısından umut verici bir yön sunmaktadır.

Keywords

• 3DP teknolojisi
• çoklu ilaç yüklü 3D çıktılar
• kişiselleştirilmiş tıp
• polipiller

AN OVERVIEW OF 3D PRINTING TECHNOLOGIES FOCUSING MULTIDRUG-LOADED 3D PRINTED DOSAGE FORMS

Abstract

Objective: This review focuses on multidrug-loaded dosage forms produced with three-dimensional printing (3DP) technologies since the confirmation of Spritam®, the first 3D printed dosage form, in 2015. Result and Discussion: The integration of multiple drugs within a single dosage form through 3DP offers substantial flexibility in design, allowing for the customization of dosage, drug release profiles, and geometric structures. These formulations offer significant design flexibility by combining different drugs in a single unit, and have the potential to optimize treatment strategies, especially for diseases requiring multiple drug use. The wide literature search reveals that the most commonly used method is Fused Deposition Modeling (FDM) to obtain 3D printed dosage forms with various geometries, such as multi-compartment capsules or tablets, bi-layered or multi-layered tablets exhibiting different release kinetics, and core/shell structured tablets. Multidrug-loaded 3D-printed dosage forms have significant potential for individualizing fixed-dose combinations and have become a promising tool for advancing personalized medicine and improving therapeutic outcomes for polypharmacy. This innovative approach can optimize therapeutic efficacy, reduce side effects, and improve patient compliance. As research continues to expand, these formulations represent a promising direction for the future of drug development and treatment strategies.

Keywords

• 3DP technology
• multidrug-loaded 3D printlets
• personalized medicine
• polypills

References

1. 1. Sultana, N., Ali, A., Waheed, A., Aqil, M. (2023). 3D Printing in pharmaceutical manufacturing: Current status and future prospects. Materials Today Communications, 38, 107987. [CrossRef]
2. 2. Jamróz, W., Szafraniec, J., Kurek, M., Jachowicz, R. (2018). 3D printing in pharmaceutical and medical applications-recent achievements and challenges. Pharmaceutical Research, 35, 1-22. [CrossRef]
3. 3. Souto, E., Campos, J., Filho, S., Teixeira, M., Martins-Gomes, C., Zielinska, A., Carbone, C., Silva, A. (2019). 3D printing in the design of pharmaceutical dosage forms. Pharmaceutical Development and Technology, 24(8), 1044-1053. [CrossRef]
4. 4. Parulski, C., Jennotte, O., Lechanteur, A., Evrard, B. (2021). Challenges of fused deposition modeling 3D printing in pharmaceutical applications: Where are we now?. Advanced Drug Delivery Reviews, 175, 113810. [CrossRef]
5. 5. Hurst, E.J. (2016). 3D printing in healthcare: Emerging applications. Journal of Hospital Librarianship, 16(3), 255-267. [CrossRef]
6. 6. Wang, Z., Yang, Y. (2021). Application of 3D printing in implantable medical devices. BioMed Research International, 2021(1), 6653967. [CrossRef]
7. 7. Jia, G., Huang, X., Tao, S., Zhang, X., Zhao, Y., Wang, H., He, J., Hao, J., Liu, B., Zhou, J. (2022). Artificial intelligence-based medical image segmentation for 3D printing and naked eye 3D visualization. Intelligent Medicine, 2(1), 48-53. [CrossRef]
8. 8. Chen, X., Possel, J.K., Wacongne, C., Van Ham, A.F., Klink, P.C., Roelfsema, P.R. (2017). 3D printing and modelling of customized implants and surgical guides for non-human primates. Journal of Neuroscience Methods, 286, 38-55. [CrossRef]

9. 9. Saydam, M., Timur, S.S., Vural, İ., Takka, S. (2022). Cell culture and pharmacokinetic evaluation of a solid dosage formulation containing a water-insoluble orphan drug manufactured by FDM-3DP technology. International Journal of Pharmaceutics, 628, 122307. [CrossRef]
10. 10. Koçak, E., Yıldız, A., Acartürk, F. (2021). Three dimensional bioprinting technology: Applications in pharmaceutical and biomedical area. Colloids and Surfaces B: Biointerfaces, 197, 111396. [CrossRef]
11. 11. Jaramillo, N., Moreno, A., Ospina, V., Lopera, A., Pelaez-Vargas, A., Cupitra, N., García, C., Paucar, C. (2023). Effect of synthesis on the antimicrobial response of β-TCP/Mg with potential applications in the regeneration of dental tissue: 3D printing of ceramic paste in a β-TCP/Mg/bioglass system. Materials Letters, 350, 134907. [CrossRef]
12. 12. Algahtani, M.S., Ahmad, J., Mohammed, A.A., Ahmad, M.Z. (2024). Extrusion-based 3D printing for development of complex capsular systems for advanced drug delivery. International Journal of Pharmaceutics, 663, 124550. [CrossRef]
13. 13. Charoo, N.A., Barakh Ali, S.F., Mohamed, E.M., Kuttolamadom, M.A., Ozkan, T., Khan, M.A., Rahman, Z. (2020). Selective laser sintering 3D printing–an overview of the technology and pharmaceutical applications. Drug Development and Industrial Pharmacy, 46(6), 869-877. [CrossRef]
14. 14. Zhu, X., Li, H., Huang, L., Zhang, M., Fan, W., Cui, L. (2020). 3D printing promotes the development of drugs. Biomedicine & Pharmacotherapy, 131, 110644. [CrossRef]
15. 15. Norman, J., Madurawe, R.D., Moore, C.M., Khan, M.A., Khairuzzaman, A. (2017). A new chapter in pharmaceutical manufacturing: 3D-printed drug products. Advanced Drug Delivery Reviews, 108, 39-50. [CrossRef]
16. 16. Saydam, M., Takka, S. (2020). Improving the dissolution of a water-insoluble orphan drug through a fused deposition modelling 3-Dimensional printing technology approach. European Journal of Pharmaceutical Sciences, 152, 105426. [CrossRef]
17. 17. Fernández-García, R., Prada, M., Bolás-Fernández, F., Ballesteros, M.P., Serrano, D.R. (2020). Oral fixed-dose combination pharmaceutical products: Industrial manufacturing versus personalized 3D printing. Pharmaceutical Research, 37, 1-22. [CrossRef]
18. 18. Chen, X., Wang, S., Wu, J., Duan, S., Wang, X., Hong, X., Han, X., Li, C., Kang, D., Wang, Z. (2022). The application and challenge of binder jet 3D printing technology in pharmaceutical manufacturing. Pharmaceutics, 14(12), 2589. [CrossRef]
19. 19. Gottschalk, N., Burkard, A., Quodbach, J., Bogdahn, M. (2023). Drop-on-powder 3D printing of amorphous high dose oral dosage forms: Process development, opportunities and printing limitations. International Journal of Pharmaceutics: X, 5, 100151. [CrossRef]
20. 20. Shi, K., Tan, D.K., Nokhodchi, A., Maniruzzaman, M. (2019). Drop-on-powder 3D printing of tablets with an anti-cancer drug, 5-fluorouracil. Pharmaceutics, 11(4), 150. [CrossRef]
21. 21. Awad, A., Fina, F., Goyanes, A., Gaisford, S., Basit, A.W. (2020). 3D printing: Principles and pharmaceutical applications of selective laser sintering. International Journal of Pharmaceutics, 586, 119594. [CrossRef]
22. 22. Deshmane, S., Kendre, P., Mahajan, H., Jain, S. (2021). Stereolithography 3D printing technology in pharmaceuticals: A review. Drug Development and Industrial Pharmacy, 47(9), 1362-1372. [CrossRef]
23. 23. Xu, X., Goyanes, A., Trenfield, S.J., Diaz-Gomez, L., Alvarez-Lorenzo, C., Gaisford, S., Basit, A.W. (2021). Stereolithography (SLA) 3D printing of a bladder device for intravesical drug delivery. Materials Science and Engineering: C, 120, 111773. [CrossRef]
24. 24. Lakkala, P., Munnangi, S.R., Bandari, S., Repka, M. (2023). Additive manufacturing technologies with emphasis on stereolithography 3D printing in pharmaceutical and medical applications: A review. International Journal of Pharmaceutics: X, 5, 100159. [CrossRef]
25. 25. Samiei, N. (2020). Recent trends on applications of 3D printing technology on the design and manufacture of pharmaceutical oral formulation: A mini review. Beni-Suef University Journal of Basic and Applied Sciences, 9(12), 1-12. [CrossRef]
26. 26. Dumpa, N., Butreddy, A., Wang, H., Komanduri, N., Bandari, S., Repka, M.A. (2021). 3D printing in personalized drug delivery: An overview of hot-melt extrusion-based fused deposition modeling. International Journal of Pharmaceutics, 600, 120501. [CrossRef]
27. 27. Rahim, T.N.A.T., Abdullah, A.M., Md Akil, H. (2019). Recent developments in fused deposition modeling-based 3D printing of polymers and their composites. Polymer Reviews, 59(4), 589-624. [CrossRef]
28. 28. Mohammed, A.A., Algahtani, M.S., Ahmad, M.Z., Ahmad, J. (2021). Optimization of semisolid extrusion (pressure-assisted microsyringe)-based 3D printing process for advanced drug delivery application. Annals of 3D Printed Medicine, 2, 100008. [CrossRef]
29. 29. Hatami, H., Mojahedian, M.M., Kesharwani, P., Sahebkar, A. (2024). Advancing personalized medicine with 3D printed combination drug therapies: A comprehensive review of application in various conditions. European Polymer Journal, 215, 113245. [CrossRef]
30. 30. Melocchi, A., Uboldi, M., Maroni, A., Foppoli, A., Palugan, L., Zema, L., Gazzaniga, A. (2020). 3D printing by fused deposition modeling of single-and multi-compartment hollow systems for oral delivery-A review. International Journal of Pharmaceutics, 579, 119155. [CrossRef]
31. 31. Chen, G., Xu, Y., Kwok, P.C.L., Kang, L. (2020). Pharmaceutical applications of 3D printing. Additive Manufacturing, 34, 101209. [CrossRef]
32. 32. Khaled, S.A., Burley, J.C., Alexander, M.R., Yang, J., Roberts, C.J. (2015). 3D printing of five-in-one dose combination polypill with defined immediate and sustained release profiles. Journal of Controlled Release, 217, 308-314. [CrossRef]
33. 33. Goyanes, A., Wang, J., Buanz, A., Martínez-Pacheco, R., Telford, R., Gaisford, S., Basit, A.W. (2015). 3D printing of medicines: Engineering novel oral devices with unique design and drug release characteristics. Molecular Pharmaceutics, 12(11), 4077-4084. [CrossRef]
34. 34. Khaled, S.A., Burley, J.C., Alexander, M.R., Yang, J., Roberts, C.J. (2015). 3D printing of tablets containing multiple drugs with defined release profiles. International Journal of Pharmaceutics, 494(2), 643-650. [CrossRef]
35. 35. Maroni, A., Melocchi, A., Parietti, F., Foppoli, A., Zema, L., Gazzaniga, A. (2017). 3D printed multi-compartment capsular devices for two-pulse oral drug delivery. Journal of Controlled Release, 268, 10-18. [CrossRef]
36. 36. Genina, N., Boetker, J.P., Colombo, S., Harmankaya, N., Rantanen, J., Bohr, A. (2017). Anti-tuberculosis drug combination for controlled oral delivery using 3D printed compartmental dosage forms: From drug product design to in vivo testing. Journal of Controlled Release, 268, 40-48. [CrossRef]
37. 37. Gioumouxouzis, C.I., Baklavaridis, A., Katsamenis, O.L., Markopoulou, C.K., Bouropoulos, N., Tzetzis, D., Fatouros, D.G. (2018). A 3D printed bilayer oral solid dosage form combining metformin for prolonged and glimepiride for immediate drug delivery. European Journal of Pharmaceutical Sciences, 120, 40-52. [CrossRef]
38. 38. Sadia, M., Isreb, A., Abbadi, I., Isreb, M., Aziz, D., Selo, A., Timmins, P., Alhnan, M.A. (2018). From ‘fixed dose combinations’ to ‘a dynamic dose combiner’: 3D printed bi-layer antihypertensive tablets. European Journal of Pharmaceutical Sciences, 123, 484-494. [CrossRef]
39. 39. Haring, A.P., Tong, Y., Halper, J., Johnson, B.N. (2018). Programming of multicomponent temporal release profiles in 3D printed polypills via core–shell, multilayer, and gradient concentration profiles. Advanced Healthcare Materials, 7(16), 1800213. [CrossRef]
40. 40. Siyawamwaya, M., du Toit, L.C., Kumar, P., Choonara, Y.E., Kondiah, P.P., Pillay, V. (2019). 3D printed, controlled release, tritherapeutic tablet matrix for advanced anti-HIV-1 drug delivery. European Journal of Pharmaceutics and Biopharmaceutics, 138, 99-110. [CrossRef]
41. 41. Robles-Martinez, P., Xu, X., Trenfield, S.J., Awad, A., Goyanes, A., Telford, R., Basit, A.W., Gaisford, S. (2019). 3D printing of a multi-layered polypill containing six drugs using a novel stereolithographic method. Pharmaceutics, 11(6), 274. [CrossRef]
42. 42. Matijašić, G., Gretić, M., Vinčić, J., Poropat, A., Cuculić, L., Rahelić, T. (2019). Design and 3D printing of multi-compartmental PVA capsules for drug delivery. Journal of Drug Delivery Science and Technology, 52, 677-686. [CrossRef]
43. 43. Pereira, B.C., Isreb, A., Forbes, R.T., Dores, F., Habashy, R., Petit, J.B., Alhnan, M.A., Oga, E.F. (2019). ‘Temporary Plasticiser’: A novel solution to fabricate 3D printed patient-centred cardiovascular ‘Polypill’architectures. European Journal of Pharmaceutics and Biopharmaceutics, 135, 94-103. [CrossRef]
44. 44. Tagami, T., Ito, E., Hayashi, N., Sakai, N., Ozeki, T. (2020). Application of 3D printing technology for generating hollow-type suppository shells. International Journal of Pharmaceutics, 589, 119825. [CrossRef]
45. 45. Trenfield, S.J., Tan, H.X., Goyanes, A., Wilsdon, D., Rowland, M., Gaisford, S., Basit, A.W. (2020). Non-destructive dose verification of two drugs within 3D printed polyprintlets. International Journal of Pharmaceutics, 577, 119066. [CrossRef]
46. 46. Keikhosravi, N., Mirdamadian, S.Z., Varshosaz, J., Taheri, A. (2020). Preparation and characterization of polypills containing aspirin and simvastatin using 3D printing technology for the prevention of cardiovascular diseases. Drug Development and Industrial Pharmacy, 46(10), 1665-1675. [CrossRef]
47. 47. Xu, X., Robles-Martinez, P., Madla, C.M., Joubert, F., Goyanes, A., Basit, A.W., Gaisford, S. (2020). Stereolithography (SLA) 3D printing of an antihypertensive polyprintlet: Case study of an unexpected photopolymer-drug reaction. Additive Manufacturing, 33, 101071. [CrossRef]
48. 48. Won, J.Y., Kim, J., Gao, G., Kim, J., Jang, J., Park, Y.H., Cho, D.W. (2020). 3D printing of drug-loaded multi-shell rods for local delivery of bevacizumab and dexamethasone: A synergetic therapy for retinal vascular diseases. Acta Biomaterialia, 116, 174-185. [CrossRef]
49. 49. Tabriz, A.G., Nandi, U., Hurt, A.P., Hui, H.W., Karki, S., Gong, Y., Kumar, S., Douroumis, D. (2021). 3D printed bilayer tablet with dual controlled drug release for tuberculosis treatment. International Journal of Pharmaceutics, 593, 120147. [CrossRef]
50. 50. Goh, W.J., Tan, S.X., Pastorin, G., Ho, P.C.L., Hu, J., Lim, S.H. (2021). 3D printing of four-in-one oral polypill with multiple release profiles for personalized delivery of caffeine and vitamin B analogues. International Journal of Pharmaceutics, 598, 120360. [CrossRef]
51. 51. Windolf, H., Chamberlain, R., Breitkreutz, J., Quodbach, J. (2022). 3D printed mini-floating-Polypill for Parkinson’s disease: Combination of levodopa, benserazide, and pramipexole in various dosing for personalized therapy. Pharmaceutics, 14(5), 931. [CrossRef]
52. 52. Zhang, B., Teoh, X.Y., Yan, J., Gleadall, A., Belton, P., Bibb, R., Qi, S. (2022). Development of combi-pills using the coupling of semi-solid syringe extrusion 3D printing with fused deposition modelling. International Journal of Pharmaceutics, 625, 122140. [CrossRef]
53. 53. Alzahrani, A., Narala, S., Youssef, A.A.A., Nyavanandi, D., Bandari, S., Mandati, P., Almotairy, A., Almutairi, M., Repka, M. (2022). Fabrication of a shell-core fixed-dose combination tablet using fused deposition modeling 3D printing. European Journal of Pharmaceutics and Biopharmaceutics, 177, 211-223. [CrossRef]
54. 54. Zhang, P., Xu, P., Chung, S., Bandari, S., Repka, M.A. (2022). Fabrication of bilayer tablets using hot melt extrusion-based dual-nozzle fused deposition modeling 3D printing. International Journal of Pharmaceutics, 624, 121972. [CrossRef]
55. 55. Alayoubi, A., Zidan, A., Asfari, S., Ashraf, M., Sau, L., Kopcha, M. (2022). Mechanistic understanding of the performance of personalized 3D-printed cardiovascular polypills: A case study of patient-centered therapy. International Journal of Pharmaceutics, 617, 121599. [CrossRef]
56. 56. Tabriz, A.G., Mithu, M.S., Antonijevic, M.D., Vilain, L., Derrar, Y., Grau, C., Morales, A., Katsamenis, O.L., Douroumis, D. (2023). 3D printing of LEGO® like designs with tailored release profiles for treatment of sleep disorder. International Journal of Pharmaceutics, 632, 122574. [CrossRef]
57. 57. Anaya, B.J., Cerda, J.R., D’Atri, R.M., Yuste, I., Luciano, F.C., Kara, A., Ruiz, H.K., Ballesteros, M.P., Serrano, D.R. (2023). Engineering of 3D printed personalized polypills for the treatment of the metabolic syndrome. International Journal of Pharmaceutics, 642, 123194. [CrossRef]
58. 58. Hu, J., Wan, J., Xi, J., Shi, W., Qian, H. (2024). AI-driven design of customized 3D-printed multi-layer capsules with controlled drug release profiles for personalized medicine. International Journal of Pharmaceutics, 656, 124114. [CrossRef]
59. 59. Zgouro, P., Katsamenis, O.L., Moschakis, T., Eleftheriadis, G.K., Kyriakidis, A.S., Chachlioutaki, K., Monou, P.K., Ntorkou, M., Zacharis, C.K., Bouropoulos, N. (2024). A floating 3D printed polypill formulation for the coadministration and sustained release of antihypertensive drugs. International Journal of Pharmaceutics, 655, 124058. [CrossRef]
60. 60. Youssef, S.H., Ganesan, R., Amirmostofian, M., Kim, S., Polara, R., Afinjuomo, F., Song, Y., Chereda, B., Singhal, N., Robinson, N. (2024). Printing a cure: A tailored solution for localized drug delivery in liver cancer treatment. International Journal of Pharmaceutics, 651, 123790. [CrossRef]
61. 61. Fuenmayor, E., O'Donnell, C., Gately, N., Doran, P., Devine, D.M., Lyons, J.G., McConville, C., Major, I. (2019). Mass-customization of oral tablets via the combination of 3D printing and injection molding. International Journal of Pharmaceutics, 569, 118611. [CrossRef]
62. 62. Ebrahimi, F., Xu, H., Fuenmayor, E., Major, I. (2024). Tailoring drug release in bilayer tablets through droplet deposition modeling and injection molding. International Journal of Pharmaceutics, 653, 123859. [CrossRef]
63. 63. McDonagh, T., Belton, P., Qi, S. (2023). Manipulating drug release from 3D printed dual-drug loaded polypills using challenging polymer compositions. International Journal of Pharmaceutics, 637, 122895. [CrossRef]
64. 64. Vivero-Lopez, M., Xu, X., Muras, A., Otero, A., Concheiro, A., Gaisford, S., Basit, A.W., Alvarez-Lorenzo, C., Goyanes, A. (2021). Anti-biofilm multi drug-loaded 3D printed hearing aids. Materials Science and Engineering: C, 119, 111606. [CrossRef]