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Development of Subdermal Implants Using Direct Powder Extrusion 3D Printing and Hot-Melt Extrusion Technologies

  • Research Article
  • Novel Advances in 3-D Printing Technology in Drug Delivery
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Abstract

Implants are drug delivery platforms that consist of a drug-polymer matrix with the ability of providing a localized and efficient controlled release of the drug with minimal side effects and achievement of the desired therapeutic outcomes with low drug loadings. Direct powder extrusion (DPE) 3D printing technology involves the extrusion of material through a nozzle of the printer in the form of pellets or powder. The present study aimed at investigating the use of the CELLINK BIO X™ bioprinter using DPE 3D printing technique to fabricate and evaluate the impact of different shapes (cuboid, cylinder, and tube) of raloxifene hydrochloride (RFH)-loaded subdermal implants on the release of RFH from the implants. This study further evaluated the impact of different processing techniques, viz., hot-melt extrusion (HME) technology vs. DPE 3D printing technique, on the release of RFH from the implants fabricated by each processing technique. All the fabricated implants were characterized by XRD, DSC, SEM, and FTIR, and evaluated for their water uptake, mass loss, and in vitro RFH release. The current study successfully demonstrated a great opportunity of controlling and/or tuning the release of RFH from the subdermal implants by altering the implant shape, and hence surface area, and could be a great contribution and/or addition to the personalization of medicines and improvement of patient compliance.

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References

  1. Stewart SA, Domínguez-Robles J, Donnelly RF, Larrañeta E. Implantable polymeric drug delivery devices: classification, manufacture, materials, and clinical applications. Polymers. 2018;10(12):1379.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Dharmayanti C, Gillam TA, Williams DB, Blencowe A. Drug-eluting biodegradable implants for the sustained release of bisphosphonates. Polymers. 2020;12(12):1–14.

    Article  Google Scholar 

  3. Zheng Y, Pokorski JK. Hot melt extrusion: an emerging manufacturing method for slow and sustained protein delivery. Nanomed Nanobiotechnol. 2021;13(5):1–23.

    Article  Google Scholar 

  4. Takahashi M, Onishi H, MacHida Y. Development of implant tablet for a week-long sustained release. J Control Release. 2004;100(1):63–74.

    Article  PubMed  Google Scholar 

  5. Solano AGR, et al. Development and evaluation of sustained-release etoposide-loaded poly(ε-caprolactone) implants. AAPS PharmSciTech. 2013;14(2):890–900.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Koutsamanis I, Spoerk M, Arbeiter F, Eder S, Roblegg E. Development of porous polyurethane implants manufactured via hot-melt extrusion. Polymers. 2020;12(12):1–22.

    Article  Google Scholar 

  7. Muhindo D, Ashour EA, Almutairi M, Repka MA. Development and evaluation of raloxifene hydrochloride-loaded subdermal implants using hot-melt extrusion technology. Int J Pharm. 2022;622(5):121834.

    Article  PubMed  Google Scholar 

  8. Manoukian OS, et al. Biodegradable polymeric injectable implants for long-term delivery of contraceptive drugs. J Appl Polym Sci. 2018;135(14):1–23.

    Article  Google Scholar 

  9. Cheng L, Lei L, Guo S. In vitro and in vivo evaluation of praziquantel loaded implants based on PEG/PCL blends. Int J Pharm. 2010;387(1–2):129–38.

    Article  PubMed  Google Scholar 

  10. Khaled SA, Burley JC, Alexander MR, Yang J, Roberts CJ. 3D printing of tablets containing multiple drugs with defined release profiles. Int J Pharm. 2015;494(2):643–50.

    Article  PubMed  Google Scholar 

  11. Abaci A, Gedeon C, Kuna A, Guvendiren M. Additive manufacturing of oral tablets: Technologies, materials and printed tablets. Pharmaceutics. 2021;13(2):1–27.

    Article  Google Scholar 

  12. Al-Dulimi Z, Wallis M, Tan DK, Maniruzzaman M, Nokhodchi A. 3D printing technology as innovative solutions for biomedical applications. Drug Discov Today. 2021;26(2):360–83.

    Article  PubMed  Google Scholar 

  13. Vithani K, Goyanes A, Jannin V, Basit AW, Gaisford S, Boyd BJ. An overview of 3D printing technologies for soft materials and potential opportunities for lipid-based drug delivery systems. Pharm Res. 2019;36(1):4.

    Article  Google Scholar 

  14. Wang J, et al. Emerging 3D printing technologies for drug delivery devices: Current status and future perspective. Adv Drug Deliv Rev. 2021;174:294–316.

    Article  PubMed  Google Scholar 

  15. Tan DK, Maniruzzaman M, Nokhodchi A. Development and optimisation of novel polymeric compositions for sustained release theophylline. Polymers. 2020;12(1):1–18.

    Google Scholar 

  16. Norman J, Madurawe RD, Moore CMV, Khan MA, Khairuzzaman A. A new chapter in pharmaceutical manufacturing: 3D-printed drug products. Adv Drug Deliv Rev. 2017;108:39–50.

    Article  PubMed  Google Scholar 

  17. Khaled SA, Burley JC, Alexander MR, Yang J, Roberts CJ. 3D printing of five-in-one dose combination polypill with defined immediate and sustained release profiles. J Control Release. 2015;217:308–14.

    Article  PubMed  Google Scholar 

  18. Edinger M, Jacobsen J, Bar-Shalom D, Rantanen J, Genina N. Analytical aspects of printed oral dosage forms. Int J Pharm. 2018;553(1–2):97–108.

    Article  PubMed  Google Scholar 

  19. Wallis M, Al-Dulimi Z, Tan DK, Maniruzzaman M, Nokhodchi A. 3D printing for enhanced drug delivery: current state-of-the-art and challenges. Drug Dev Ind Pharm. 2020;46(9):1385–401.

    Article  PubMed  Google Scholar 

  20. Chen G, Xu Y, Kwok PCL, Kang L. Pharmaceutical applications of 3D printing. Addit Manuf. 2020;34(4):101209.

    Google Scholar 

  21. Tool R, et al. Novel on-demand 3-dimensional (3D) printed tablets using fill density as an effective release-controlling tool. Polymers. 2020;12(1872):1–21.

    Google Scholar 

  22. Rahim TNAT, Abdullah AM, Md Akil H. Recent developments in fused deposition modeling-based 3D printing of polymers and their composites. Polym Rev. 2019;59(4):589–624.

  23. Cui M, et al. Exploration and preparation of patient-specific ciprofloxacin implants drug delivery system via 3D printing technologies. J Pharm Sci. 2021;110(11):3678–89.

    Article  PubMed  Google Scholar 

  24. Bandari S, Nyavanandi D, Dumpa N, Repka MA. Coupling hot melt extrusion and fused deposition modeling: critical properties for successful performance. Adv Drug Deliv Rev. 2021;172:52–63.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Long J, Gholizadeh H, Lu J, Bunt C, Seyfoddin A. Application of fused deposition modelling (FDM) method of 3D printing in drug delivery. Curr Pharm Des. 2017;23(3):433–9.

    Article  PubMed  Google Scholar 

  26. Keikhosravi N, Mirdamadian SZ, Varshosaz J, Taheri A. Preparation and characterization of polypills containing aspirin and simvastatin using 3D printing technology for the prevention of cardiovascular diseases. Drug Dev Ind Pharm. 2020;46(10):1665–75.

    Article  PubMed  Google Scholar 

  27. Oladeji SA, Dadou SM, Zhao M, Li S, Jones DS, Andrews GP. The development and optimisation of gastro-retentive floating tablets using fused deposition modelling 3D printing. J Pharm Pharmacol. 2022;176(3):1–17.

    Google Scholar 

  28. Manini G, Benali S, Mathew A, Napolitano S, Raquez JM, Goole J. Paliperidone palmitate as model of heat-sensitive drug for long-acting 3D printing application. Int J Pharm. 2022;618(3):121662.

    Article  PubMed  Google Scholar 

  29. Gültekin HE, Tort S, Tuğcu-Demiröz F, Acartürk F. 3D printed extended release tablets for once daily use: an in vitro and in vivo evaluation study for a personalized solid dosage form. Int J Pharm. 2021;596(1):120222.

    Article  PubMed  Google Scholar 

  30. Lamichhane S, Park J, Sohn DH, Lee S. Customized novel design of 3D printed pregabalin tablets for intra-gastric floating and controlled release using FDM. Pharmaceutics. 2019;11(11):564.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Shi K, Slavage JP, Maniruzzaman M, Nokhodchi A. Role of release modifiers to modulate drug release from fused deposition modelling (FDM) 3D printed tablets. Int J Pharm. 2021;597(3):120315.

    Article  PubMed  Google Scholar 

  32. Vaz VM, Kumar L. 3D printing as a promising tool in personalized medicine. AAPS PharmSciTech. 2021;22:1–20.

    Article  Google Scholar 

  33. Farmer ZL, et al. 3D printed estradiol-eluting urogynecological mesh implants: Influence of material and mesh geometry on their mechanical properties. Int J Pharm. 2021;593(11):120145.

    Article  PubMed  Google Scholar 

  34. Zhao X, Wei W, Niu R, Li Q, Hu C, Jiang S. 3D printed intragastric floating and sustained-release tablets with air chambers. J Pharm Sci. 2022;111(1):116–23.

    Article  PubMed  Google Scholar 

  35. Mirdamadian SZ, Varshosaz J, Minaiyan M, Taheri A. 3D printed tablets containing oxaliplatin loaded alginate nanoparticles for colon cancer targeted delivery. An in vitro/in vivo study. Int J Biol Macromol. 2022;205(2):90–109.

    Article  PubMed  Google Scholar 

  36. Krause J, Müller L, Sarwinska D, Seidlitz A, Sznitowska M, Weitschies W. 3D printing of mini tablets for pediatric use. Pharmaceuticals. 2021;14(2):1–16.

    Article  Google Scholar 

  37. Yang Y, et al. 3D-printed polycaprolactone-chitosan based drug delivery implants for personalized administration. Mater Des. 2022;214(2):110394.

    Article  Google Scholar 

  38. Li R, Pan Y, Chen D, Xu X, Yan G, Fan T. Design, preparation and in vitro evaluation of core–shell fused deposition modelling 3D-printed verapamil hydrochloride pulsatile tablets. Pharmaceutics. 2022;14(2):437.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Fanous M, et al. Development of immediate release 3D-printed dosage forms for a poorly water-soluble drug by fused deposition modeling: Study of morphology, solid state and dissolution. Int J Pharm. 2021;599:120417.

    Article  PubMed  Google Scholar 

  40. Cailleaux S, Sanchez-Ballester NM, Gueche YA, Bataille B, Soulairol I. Fused deposition modeling (FDM), the new asset for the production of tailored medicines. J Control Release. 2021;330(7):821–41.

    Article  PubMed  Google Scholar 

  41. Okwuosa TC, Soares C, Gollwitzer V, Habashy R, Timmins P, Alhnan MA. On demand manufacturing of patient-specific liquid capsules via co-ordinated 3D printing and liquid dispensing. Eur J Pharm Sci. 2018;118(3):134–43.

    Article  PubMed  Google Scholar 

  42. Isreb A, Baj K, Wojsz M, Isreb M, Peak M, Alhnan MA. 3D printed oral theophylline doses with innovative ‘radiator-like’ design: impact of polyethylene oxide (PEO) molecular weight. Int J Pharm. 2019;564(4):98–105.

    Article  PubMed  Google Scholar 

  43. Verstraete G, et al. 3D printing of high drug loaded dosage forms using thermoplastic polyurethanes. Int J Pharm. 2018;536(1):318–25.

    Article  PubMed  Google Scholar 

  44. Gorkem Buyukgoz G, Soffer D, Defendre J, Pizzano GM, Davé RN. Exploring tablet design options for tailoring drug release and dose via fused deposition modeling (FDM) 3D printing. Int J Pharm. 2020;591(7):119987.

  45. Đuranović M, Obeid S, Madžarević M, Cvijić S, Ibrić S. Paracetamol extended release FDM 3D printlets: evaluation of formulation variables on printability and drug release. Int J Pharm. 2021;592(7):120053.

    Article  PubMed  Google Scholar 

  46. Ong JJ, et al. 3D printed opioid medicines with alcohol-resistant and abuse-deterrent properties. Int J Pharm. 2020;579(1):119169.

    Article  PubMed  Google Scholar 

  47. Pistone M, et al. Direct cyclodextrin-based powder extrusion 3D printing for one-step production of the BCS class II model drug niclosamide. Drug Deliv Transl Res. 2022;12(8):1895–910.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Goyanes A, Allahham N, Trenfield SJ, Stoyanov E, Gaisford S, Basit AW. Direct powder extrusion 3D printing: fabrication of drug products using a novel single-step process. Int J Pharm. 2019;567(6):118471.

    Article  PubMed  Google Scholar 

  49. Boniatti J, et al. Direct powder extrusion 3d printing of praziquantel to overcome neglected disease formulation challenges in paediatric populations. Pharmaceutics. 2021;13(8):1114.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Mendibil X, Tena G, Duque A, Uranga N, Campanero MÁ, Alonso J. Direct powder extrusion of paracetamol loaded mixtures for 3d printed pharmaceutics for personalized medicine via low temperature thermal processing. Pharmaceutics. 2021;13(6):907.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Fanous M, Gold S, Muller S, Hirsch S, Ogorka J, Imanidis G. Simplification of fused deposition modeling 3D-printing paradigm: Feasibility of 1-step direct powder printing for immediate release dosage form production. Int J Pharm. 2020;578(2):119124.

    Article  PubMed  Google Scholar 

  52. Kuźmińska M, et al. Solvent-free temperature-facilitated direct extrusion 3D printing for pharmaceuticals. Int J Pharm. 2021;598(10):1–9.

    Google Scholar 

  53. Annaji M, et al. Application of extrusion-based 3D printed dosage forms in the treatment of chronic diseases. J Pharm Sci. 2020;109(12):3551–68.

    Article  PubMed  Google Scholar 

  54. Sánchez-Guirales SA, Jurado N, Kara A, Lalatsa A, Serrano DR. Understanding direct powder extrusion for fabrication of 3d printed personalised medicines: a case study for nifedipine minitablets. Pharmaceutics. 2021;13(10):1583.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Stewart SA, et al. Development of a biodegradable subcutaneous implant for prolonged drug delivery using 3D printing. Pharmaceutics. 2020;12(2):105.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Tappa K, et al. Medication eluting devices for the field of OBGYN (MEDOBGYN): 3D printed biodegradable hormone eluting constructs, a proof of concept study. PLoS ONE. 2017;12(8):1–17.

    Article  Google Scholar 

  57. Kempin W, et al. Assessment of different polymers and drug loads for fused deposition modeling of drug loaded implants. Eur J Pharm Biopharm. 2017;115(6):84–93.

    Article  PubMed  Google Scholar 

  58. Wang Y, et al. 3D printed biodegradable implants as an individualized drug delivery system for local chemotherapy of osteosarcoma. Mater Des. 2020;186(1):108336.

    Article  Google Scholar 

  59. Liaskoni A, Wildman RD, Roberts CJ. 3D printed polymeric drug-eluting implants. Int J Pharm. 2021;597(12):120330.

    Article  PubMed  Google Scholar 

  60. Vo AQ, Zhang J, Nyavanandi D, Bandari S, Repka MA. Hot-melt extrusion paired fused deposition modeling 3D printing to develop hydroxypropyl cellulose based floating tablets of cinnarizine. Carbohyd Polym. 2020;246(15):139–48.

    Google Scholar 

  61. Narala S, Nyavanandi D, Alzahrani A, Bandari S, Zhang F, Repka MA. Creation of hydrochlorothiazide pharmaceutical cocrystals via hot-melt extrusion for enhanced solubility and permeability. AAPS PharmSciTech. 2022;23(1):1–11.

    Article  Google Scholar 

  62. Li D, et al. PLA/F68/Dexamethasone implants prepared by hot-melt extrusion for controlled release of anti-inflammatory drug to implantable medical devices: I. Preparation, characterization and hydrolytic degradation study. Int J Pharm. 2013;441(1–2):365–72.

    Article  PubMed  Google Scholar 

  63. Balik BA, Argin S, Lagaron JM, Torres-Giner S. Preparation and characterization of electrospun pectin-based films and their application in sustainable aroma barrier multilayer packaging. Appl Sci. 2019;9(23):5136.

    Article  Google Scholar 

  64. Quinten T, De Beer T, Vervaet C, Remon JP. Evaluation of injection moulding as a pharmaceutical technology to produce matrix tablets. Eur J Pharm Biopharm. 2009;71(1):145–54.

    Article  PubMed  Google Scholar 

  65. Andrews GP, Jones DS, Diak OA, McCoy CP, Watts AB, McGinity JW. The manufacture and characterisation of hot-melt extruded enteric tablets. Eur J Pharm Biopharm. 2008;69(1):264–73.

    Article  PubMed  Google Scholar 

  66. Banker GS, Rhodes CT. Modern pharmaceutics. Boca Raton: Taylor & Francis Group; 2019. p. 105–12.

    Google Scholar 

  67. Baishya H. Application of mathematical models in drug release kinetics of carbidopa and levodopa ER tablets. J Dev Drugs. 2017;06(02):1–8.

    Article  Google Scholar 

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Acknowledgements

This project was also partially supported by Grant Number P30GM122733-01A1, funded by the National Institute of General Medical Sciences (NIGMS) a component of the National Institutes of Health (NIH) as one of its Centers of Biomedical Research Excellence (COBRE).

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Authors and Affiliations

  1. Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, Mississippi, 38677, USA

    Derick Muhindo, Eman A. Ashour, Mashan Almutairi & Michael A. Repka

  2. Department of Pharmaceutics, College of Pharmacy, University of Hail, 81442, Hail, Saudi Arabia

    Mashan Almutairi

  3. Pii Center for Pharmaceutical Technology, School of Pharmacy, University of Mississippi, University, Mississippi, 38677, USA

    Michael A. Repka

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  1. Derick Muhindo
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  2. Eman A. Ashour
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Contributions

Derick Muhindo: Study conception and design, conduct laboratory experiments, analyze experimental data collected, interpretation of results, manuscript writing/preparation.

Eman A. Ashour: Review and approve the study conception and design, review set up of laboratory experiments, review data and results generated from laboratory experiments, review the drafted manuscript and provide feedback to have the final manuscript ready for submission to the journal.

Mashan Almutairi: Assist in designing and conducting laboratory experiments.

Michael A. Repka: Review and approve the study conception and design, review set up of laboratory experiments, review data and results generated from laboratory experiments, review and approve the final manuscript for submission to the journal.

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Correspondence to Michael A. Repka.

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Muhindo, D., Ashour, E.A., Almutairi, M. et al. Development of Subdermal Implants Using Direct Powder Extrusion 3D Printing and Hot-Melt Extrusion Technologies. AAPS PharmSciTech 24, 215 (2023). https://doi.org/10.1208/s12249-023-02669-7

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