3D-Printed Network Structures as Controlled-Release Drug Delivery Systems: Dose Adjustment, API Release Analysis and Prediction

Abstract

3D printing evolved as a promising technique to improve individualization of drug therapy. In particular, when printing sustained release solid dosage forms, as for instance implants, inserts, and also tablets, estimation of the drug release profile in vivo is necessary. In most cases, corresponding analyses cannot be performed at hospital or community pharmacies. Therefore, the present study aimed to develop a sustained release drug delivery system produced via 3D printing, which allows dose adaption and estimation of drug release at the same time. Filaments as feedstock for the printer were produced via hot-melt extrusion and consisted of Eudragit® RL as sustained release polymer, 30% theophylline as model active pharmaceutical ingredient, and stearic acid as solid plasticizer. Assuming that the surface/mass ratio was constant, network structures of different densities were printed as novel solid dosage form. Their weight (263 to 668 mg), thereby their dose, and surface area, determined using X-ray microcomputed tomography, showed a linear correlation with the fill density. The specific surface area of the network hardly varied with changing fill density. Dissolution studies showed a slower drug release for dosage forms with a denser network. Higuchi’s model was used for prediction of drug release and showed limited applicability due to different release kinetics for different fill densities. However, using linear interpolation for the prediction resulted in good RMSEP values between 1.4 and 3.7%. These findings might be useful to enable customized production of sustained release solid dosage forms via 3D printing in hospital and community pharmacies in the future.

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Abbreviations

API:

Active pharmaceutical ingredient

CT:

Computed tomography

DSC:

Differential scanning calorimetry

EC:

Ethyl cellulose

FDM:

Fused deposition modeling

HME:

Hot-melt extrusion

HPMC:

Hydroxypropyl methylcellulose

RMSEP:

Root mean square error of prediction

SSA:

Specific surface area

2. References

  1. 1.

    Schlender JF, Meyer M, Thelen K, Krauss M, Willmann S, Eissing T, et al. Development of a whole-body physiologically based pharmacokinetic approach to assess the pharmacokinetics of drugs in elderly individuals. Clin Pharmacokinet. 2016;55(12):1573–89. https://doi.org/10.1007/s40262-016-0422-3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Klotz U. The elderly—a challenge for appropriate drug treatment. Eur J Clin Pharmacol. 2008;64(3):225–6. https://doi.org/10.1007/s00228-007-0410-5.

    Article  PubMed  Google Scholar 

  3. 3.

    Breitkreutz J, Boos J. Paediatric and geriatric drug delivery. Expert Opin Drug Deliv. 2007;4(1):37–45. https://doi.org/10.1517/17425247.4.1.37.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology - drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157–67. https://doi.org/10.1056/NEJMra035092.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Wening K, Breitkreutz J. Oral drug delivery in personalized medicine: Unmet needs and novel approaches. Int J Pharm. 2011;404(1–2):1–9. https://doi.org/10.1016/j.ijpharm.2010.11.001.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Wening K, Breitkreutz J. Novel delivery device for monolithical solid oral dosage forms for personalized medicine. Int J Pharm. 2010;395(1–2):174–81. https://doi.org/10.1016/j.ijpharm.2010.05.036.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Laukamp EJ, Knop K, Thommes M, Breitkreutz J. Micropellet-loaded rods with dose-independent sustained release properties for individual dosing via the solid dosage pen. Int J Pharm. 2016;499(1–2):271–9. https://doi.org/10.1016/j.ijpharm.2016.01.001.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Giannatsis J, Dedoussis V. Additive fabrication technologies applied to medicine and health care: a review. Int J Adv Manuf Technol. 2009;40(1–2):116–27. https://doi.org/10.1007/s00170-007-1308-1.

    Article  Google Scholar 

  9. 9.

    Tiwari RV, Patil H, Repka MA. Contribution of hot-melt extrusion technology to advance drug delivery in the 21st century. Expert Opin Drug Deliv. 2016;13(3):451–64. https://doi.org/10.1517/17425247.2016.1126246.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Pietrzak K, Isreb A, Alhnan MA. A flexible-dose dispenser for immediate and extended release 3D printed tablets. Eur J Pharm Biopharm. 2015;96:380–7. https://doi.org/10.1016/j.ejpb.2015.07.027.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Skowyra J, Pietrzak K, Alhnan MA. Fabrication of extended-release patient-tailored prednisolone tablets via fused deposition modelling (FDM) 3D printing. Eur J Pharm Sci. 2015;68:11–7. https://doi.org/10.1016/j.ejps.2014.11.009.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Goyanes A, Det-Amornrat U, Wang J, Basit AW, Gaisford S. 3D scanning and 3D printing as innovative technologies for fabricating personalized topical drug delivery systems. J Control Release. 2016;234:41–8. https://doi.org/10.1016/j.jconrel.2016.05.034.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Goyanes A, Robles Martinez P, Buanz A, Basit AW, Gaisford S. Effect of geometry on drug release from 3D printed tablets. Int J Pharm. 2015;494(2):657–63. https://doi.org/10.1016/j.ijpharm.2015.04.069.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Masood SH, Singh S (eds) Design of micro-features in polymeric drug delivery devices using FDM. ASME International Mechanical Engineering Congress and Exposition. Proceedings (IMECE). 2007.

  15. 15.

    Zhang J, Feng X, Patil H, Tiwari RV, Repka MA. Coupling 3D printing with hot-melt extrusion to produce controlled-release tablets. Int J Pharm. 2017;519(1–2):186–97. https://doi.org/10.1016/j.ijpharm.2016.12.049.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Melocchi A, Parietti F, Maroni A, Foppoli A, Gazzaniga A, Zema L. Hot-melt extruded filaments based on pharmaceutical grade polymers for 3D printing by fused deposition modeling. Int J Pharm. 2016;509(1–2):255–63. https://doi.org/10.1016/j.ijpharm.2016.05.036.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Zhang J, Yang W, Vo AQ, Feng X, Ye X, Kim DW, et al. Hydroxypropyl methylcellulose-based controlled release dosage by melt extrusion and 3D printing: structure and drug release correlation. Carbohydr Polym. 2017;177:49–57. https://doi.org/10.1016/j.carbpol.2017.08.058.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Kavanagh N, Corrigan OI. Swelling and erosion properties of hydroxypropylmethylcellulose (Hypromellose) matrices—influence of agitation rate and dissolution medium composition. Int J Pharm. 2004;279(1–2):141–52. https://doi.org/10.1016/j.ijpharm.2004.04.016.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Sun Y, Soh S. Printing tablets with fully customizable release profiles for personalized medicine. Adv Mater. 2015;27(47):7847–53. https://doi.org/10.1002/adma.201504122.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Goyanes A, Fina F, Martorana A, Sedough D, Gaisford S, Basit AW. Development of modified release 3D printed tablets (printlets) with pharmaceutical excipients using additive manufacturing. Int J Pharm. 2017;527(1–2):21–30. https://doi.org/10.1016/j.ijpharm.2017.05.021.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Okwuosa TC, Pereira BC, Arafat B, Cieszynska M, Isreb A, Alhnan MA. Fabricating a Shell-Core delayed release tablet using dual FDM 3D printing for patient-Centred therapy. Pharm Res. 2017;34(2):427–37. https://doi.org/10.1007/s11095-016-2073-3.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Kempin W, Franz C, Koster L-C, Schneider F, Bogdahn M, Weitschies W, et al. Assessment of different polymers and drug loads for fused deposition modeling of drug loaded implants. Eur J Pharm Biopharm. 2017;115:84–93. https://doi.org/10.1016/j.ejpb.2017.02.014.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Kyobula M, Adedeji A, Alexander MR, Saleh E, Wildman R, Ashcroft I, et al. 3D inkjet printing of tablets exploiting bespoke complex geometries for controlled and tuneable drug release. J Control Release. 2017;261:207–15. https://doi.org/10.1016/j.jconrel.2017.06.025.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Goyanes A, Buanz ABM, Basit AW, Gaisford S. Fused-filament 3D printing (3DP) for fabrication of tablets. Int J Pharm. 2014;476(1):88–92. https://doi.org/10.1016/j.ijpharm.2014.09.044.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Li Q, Guan X, Cui M, Zhu Z, Chen K, Wen H, et al. Preparation and investigation of novel gastro-floating tablets with 3D extrusion-based printing. Int J Pharm. 2018;535(1):325–32. https://doi.org/10.1016/j.ijpharm.2017.10.037.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Yang Y, Wang H, Li H, Ou Z, Yang G. 3D printed tablets with internal scaffold structure using ethyl cellulose to achieve sustained ibuprofen release. Eur J Pharm Sci. 2018;115:11–8. https://doi.org/10.1016/j.ejps.2018.01.005.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Thakral S, Thakral NK, Majumdar DK. Eudragit®: a technology evaluation. Expert Opin Drug Deliv. 2013;10(1):131–49. https://doi.org/10.1517/17425247.2013.736962.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Quinten T, Andrews GP, De Beer T, Saerens L, Bouquet W, Jones DS, et al. Preparation and evaluation of sustained-release matrix tablets based on metoprolol and an acrylic carrier using injection moulding. AAPS PharmSciTech. 2012;13(4):1197–211. https://doi.org/10.1208/s12249-012-9848-6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Korte C, Quodbach J. Formulation development and process analysis of drug-loaded filaments manufactured via hot-melt extrusion for 3D-printing of medicines. Pharm Dev Technol. 2018:1–11. https://doi.org/10.1080/10837450.2018.1433208.

    CAS  Article  Google Scholar 

  30. 30.

    European Directorate for the Quality of Medicines & HealthCare. Monograph 51701: Recommendations on dissolution testing. European Pharmacopoeia 9.0 ed. Strasbourg: European Directorate for the Quality of Medicines & HealthCare; 2017. p. 761–763.

  31. 31.

    Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm. 1983;15(1):25–35. https://doi.org/10.1016/0378-5173(83)90064-9.

    CAS  Article  Google Scholar 

  32. 32.

    Higuchi T. Mechanism of sustained-action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci. 1963;52(12):1145–9. https://doi.org/10.1002/jps.2600521210.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Barimani S, Kleinebudde P. Monitoring of tablet coating processes with colored coatings. Talanta. 2018;178:686–97. https://doi.org/10.1016/j.talanta.2017.10.008.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Higuchi T. Rate of release of medicaments from ointment bases containing drugs in suspension. J Pharm Sci. 1961;50(10):874–5. https://doi.org/10.1002/jps.2600501018.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001;13(2):123–33. https://doi.org/10.1016/S0928-0987(01)00095-1.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Siepmann J, Siepmann F. Modeling of diffusion controlled drug delivery. J Control Release. 2012;161(2):351–62. https://doi.org/10.1016/j.jconrel.2011.10.006.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Dorothee Eikeler for her support in the content determination of the matrices, Stefan Stich for preparing in-house-built sinkers, and Karin Matthée for conduction of DSC measurements. Further, Raphael Wiedey is acknowledged for his support in the conduction and evaluation of measurements using X-ray microcomputed tomography.

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Correspondence to Julian Quodbach.

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Guest Editors: Niklas Sandler and Jukka Rantanen

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Korte, C., Quodbach, J. 3D-Printed Network Structures as Controlled-Release Drug Delivery Systems: Dose Adjustment, API Release Analysis and Prediction. AAPS PharmSciTech 19, 3333–3342 (2018). https://doi.org/10.1208/s12249-018-1017-0

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Key words

  • 3D printing
  • dissolution analysis and prediction
  • extended release matrix
  • personalized medicine
  • advanced drug delivery system