Biomedical Microdevices

, Volume 14, Issue 3, pp 583–593

Controlled release of bupivacaine HCl through microchannels of biodegradable drug delivery device



Local and prolonged delivery of local analgesics is much desired for post-operative pain management. For delivery of local analgesics at a constant rate over couple of days, a microfluidic device comprised of a drug reservoir and microchannels for drug release was developed using a biodegradable polymer, 85/15 poly(lactic-co-glycolic acid). Unlike conventional methods relying on material property, this device enables convenient modulation of the release speed of drugs by a simple change of the channel geometry such as the length and cross-sectional area. Bupivacaine was selected as our model local analgesic drug and its diffusional transport through microchannels was studied using the microfluidic devices. However, since the salt form of bupivacaine, bupivacaine hydrochloride, has pH-dependent solubility, its precipitation in microchannels had an adverse impact on the release performance of the microfluidic drug delivery devices. Thus, in this investigation, the diffusional transport and precipitation of bupivacaine hydrochloride in microfluidic channels were studied using in vitro release experiments and optical analysis. Furthermore, a concept of co-delivery of bupivacaine hydrochloride together with acidic additives was demonstrated to achieve a zero-order delivery of bupivacaine hydrochloride without the clogging of microchannels by its precipitation.


Drug delivery Microchannels Drug reservoir Bupivacaine Diffusion pH-dependent solubility 


  1. F. Brounéus, K. Karami, P. Beronius, L.-O. Sundelöf, Diffusive transport properties of some local anesthetics applicable for iontophoretic formulation of the drugs. Int. J. Pharm. 218, 57–62 (2001)CrossRefGoogle Scholar
  2. P.-C. Chen, Y.J. Park, L.-C. Chang, D.S. Kohane, R.H. Bartlett, R. Langer, V.C. Yang, Injectable microparticle-gel system for prolonged and localized lidocaine release. I. In vitro characterization. J. Biomed. Mater. Res. 70A, 412–419 (2004)CrossRefGoogle Scholar
  3. J. Curley, J. Castillo, J. Hotz, M. Uezono, S. Hernandez, J.-O. Lim, J. Tinger, M. Chasin, R. Langer, C. Berde, Prolonged regional nerve blockade:injectable biodegradable bupivcaine/polyester microspheres. Anesthesiology 84, 1401–1410 (1996)CrossRefGoogle Scholar
  4. T.A. Desai, D.J. Hansford, L. Kulinsky, A.H. Nashat, G. Rasi, J. Tu, Y. Wang, M. Zhang, M. Ferrari, Nanopore technology for biomedical applications. Biomed. Microdev. 2, 11–40 (1999)CrossRefGoogle Scholar
  5. C. Drager, D. Benziger, F. Gao, C.B. Berde, Prolonged intercoastal nerve blockade in sheep using controlled-release of bupivacaine and dexamethasone from polymer microspheres. Anesthesiology 89, 969–979 (1998)CrossRefGoogle Scholar
  6. H. Epstein-Barash, I. Shichor, A.H. Kwon, S. Hall, M.W. Lawlor, R. Langer, D.S. Kohane, Prolonged duration local anesthesia with minimal toxicity. P. Natl. Acad. Sci. USA 106, 7125–7130 (2009)CrossRefGoogle Scholar
  7. K. King, C. Wang, M. Kaazempur-Mofrad, J. Vacanti, J. Borenstein, Biodegradable microfluidics. Adv. Mater. 16, 2007–2012 (2004)CrossRefGoogle Scholar
  8. D.S. Kohane, S.E. Smith, D.N. Louis, G. Colombo, P. Ghoroghchian, N.G.M. Hunfeld, C.B. Berde, R. Langer, Prolonged duration local anesthesia from tetrodotoxin-enhanced local anesthetic microspheres. Pain 104, 415–421 (2003)CrossRefGoogle Scholar
  9. D.S. Kohane, J.Y. Tse, Y. Yeo, R. Padera, M. Shubina, R. Langer, Biodegradable polymeric microspheres and nanospheres for drug delivery in the peritoneum. J. Biomed. Mater. Res. 77A, 351–361 (2006)CrossRefGoogle Scholar
  10. D.J. Kopacz, P.G. Lacouture, D. Wu, P. Nandy, R. Swanton, C. Landau, The dose response and effects of dexamethasone on bupivacaine microcapsules for intercostal vlockade (T9 to T11) in healthy volunteers. Ansth. Analg. 96, 576–582 (2000)Google Scholar
  11. D.J. Kopacz, C.M. Bernards, H.W. Allen, C. Landau, P. Nandy, D. Wu, P.G. Lacouture, A model to evaluate the pharmacokinetic and pharmacodynamic variables of extended-release products using in vivo tissue microdialysis in humans: bupivacaine-loaded microcapsules. Anesth. Analg. 97, 124–131 (2003)CrossRefGoogle Scholar
  12. F. Martin, R. Walczak, A. Boiarski, M. Cohen, T. West, C. Cosentino, M. Ferrari, Tailoring width of microfabricated nanochannels to solute size can be used to control diffusion kinetics. J. Control. Rel. 102, 123–133 (2005)CrossRefGoogle Scholar
  13. R. Padera, E. Bellas, J.Y. Tse, D. Hao, D.S. Kohane, Local myotoxicity from sustained release of bupivacaine from microparticles. Anesthsiology 108, 921–928 (2008)CrossRefGoogle Scholar
  14. J.L. Pedersen, J. Lillesø, N.A. Hammer, M.U. Werner, K. Holte, P.G. Lacouture, H. Kehlet, Bupivacaine in microcapsules prolongs analgesia after subcutaneous infiltration in humans: a dose-finding study. Anesth. Analg. 99, 912–918 (2004)CrossRefGoogle Scholar
  15. W. Ryu, R.J. Fasching, M. Vyakarnam, R.S. Greco, F.B. Prinz, Microfabrication technology of biodegradable polymers for interconnecting microstructures. J. Microelectromech. Syst. 15, 1457–1465 (2006)CrossRefGoogle Scholar
  16. W. Ryu, S.W. Min, K.E. Hammerick, M. Vyakarnam, R.S. Greco, F.B. Prinz, R.J. Fasching, The construction of three-dimensional microfluidic scaffolds of biodegradable polymers by solvent vapor based bonding of micro-molded layers. Biomaterials 28, 1174–1184 (2007a)CrossRefGoogle Scholar
  17. W. Ryu, Z. Huang, F.B. Prinz, S.B. Goodman, R.J. Fasching, Biodegradable micro-osmotic pump for long-term and controlled release of basic fibroblast growth factor. J. Control. Rel. 124, 98–105 (2007b)CrossRefGoogle Scholar
  18. W.H. Ryu, M. Vyakarnam, R.S. Greco, F.B. Prinz, R.J. Fasching, Fabrication of multi-layered biodegradable drug delivery device based on micro-structuring of PLGA polymers. Biomed. Microdev. 9, 845–53 (2007c)CrossRefGoogle Scholar
  19. A.A. Saber, M.H. Elgamal, A.J. Rao, E.A. Itawi, R.L. Martinez, Early experience with lidocaine patch for postoperative pain control after laparoscopic ventral hernia repair. Int. Surg. 7, 36–38 (2009)CrossRefGoogle Scholar
  20. S. Sato, Y. Baba, K. Tajima, T. Kimura, M.H. Tsuji, Y. Kohda, Y. Sato, Prolongation of epidural anesthesia in the rabbit with the use of biodegradable copolymer paste containing lidocaine. Anesth. Analg. 80, 97–101 (1995)Google Scholar
  21. J.C. Shah, M. Maniar, pH-Dependent solubility and dissociation of bupivacaine and its relevance to the formulation of a controlled release. J. Control. Release 23, 261–270 (1993)CrossRefGoogle Scholar
  22. J. Shah, J. Johnston, H. Krum, S. Halladay, D. Lissin, N. Verity, Pharmaceutical characteristics of SABERTM-Bupivacaine (PosidurTM) formulation in humans. The J of Pain 8(Supplemental), S46 (2007)CrossRefGoogle Scholar
  23. I. Silva, V. Veredas, M. Carpes, C. Santana, Chromatographic separation of bupivacaine enatiomers by HPLC: parameters estimation of equilibrium and mass transfer under linear conditions. Adsorption 7, 123–129 (2005)CrossRefGoogle Scholar
  24. A. Sykuła-Zając, E. Łodyaga-Chruścińska, B. Pałecz, R.E. Dinnebier, U.J. Griesser, V. Niederwanger, Thermal and X-ray analysis of racemic bupivacaine hydrochloride. J. Therm. Anal. Calorim. 105, 1031–1036 (2011)CrossRefGoogle Scholar
  25. A.S. Tatavarti, S.W. Hoag, Micro-environmental pH modulation based release enhancement of a weakly basic drug from hydrophilic matrices. J. Pharm. Sci. 95, 1459–1468 (2006)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.School of Mechanical EngineeringYonsei UniversitySeoulRepublic of Korea

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