Poly(lactic-co-glycolic acid) microparticles in fibrin glue for local, sustained delivery of bupivacaine

Se-Na Kim; Byeong Hyeon Choi; Hyun Koo Kim; Young Bin Choy

Journal of Industrial and Engineering Chemistry, Vol.75, 86-92, July, 2019

DOI10.1016/j.jiec.2019.02.028 Export Citation

Poly(lactic-co-glycolic acid) microparticles in fibrin glue for local, sustained delivery of bupivacaine

Se-Na Kim¹, Byeong Hyeon Choi^{2, 3}, Hyun Koo Kim^{2, 3, †}, and Young Bin Choy^{1, 4, †}

¹Interdisciplinary Program in Bioengineering, College of Engineering, Seoul National University, Seoul 08826, Republic of Korea
²Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02841, Republic of Korea
³Department of Thoracic and Cardiovascular Surgery, Korea University Guro Hospital, College of Medicine, Korea University, Seoul 08308, Republic of Korea
⁴Institute of Medical & Biological Engineering, Medical Research Center, Seoul National University, Seoul 03080, Republic of Korea

E-mail:,

To control postoperative pain, a bolus solution of anesthetic drugs is often injected locally, which, however, is limited by short-term drug efficacy and low bioavailability. To resolve this, we propose a composite formulation of bupivacaine-loaded poly(lactic-co-glycolic acid) microparticles (BPC-MPs) and fibrin glue. We prepared the BPC-MPs using the emulsion method and formulated them with fibrin glue to produce FG_BPC-MPs. We performed in vitro drug release experiments for 35 days with the formulations in pH 7.4 phosphate buffered saline (PBS) at 37 °C. To evaluate in vivo pain-relief efficacy, the pain-induced animals via L5-spinal nerve ligation were treated with FG_BPC-MPs, as well as the control formulations, and the paw withdrawal latency was evaluated with the von Frey filament test. The FG_BPC-MPs exhibited a sustained drug release with a reduced initial burst for up to 35 days. When tested in vivo, a dramatic increase in paw withdrawal threshold was observed during the entire 10-day testing period, suggesting that the pain-relief efficacy was improved and prolonged compared with that for the other control formulations. The FG_BPC-MPs loaded with bupivacaine can be a promising formulation for the treatment of local, persistent pain after surgery.

Keywords:Bupivacaine;Fibrin glue;Local anesthetic;Microparticles;Sustained delivery

[References]

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Kandil E, Melikman E, Adinoff B, J. Anesth. Clin. Res., 8, 697 (2017)
Wu CL, Cohen SR, Richman JM, Rowlingson AJ, Courpas GE, Cheung K, Lin EE, Liu SS, Anesthesiology, 103, 1079 (2005)
Santamaria CM, Woodruff A, Yang R, Kohane DS, Mater. Today, 20, 22 (2017)
Ekholm O, Kurita GP, Højsted J, Juel K, Sjøgren P, Pain, 155, 2486 (2014)
Kuip EJ, Oldenmenger WH, Visser-Thijs MF, de Bruijn P, Oomen-de Hoop E, Mathijssen RH, Van der Rijt CC, Koolen SW, Oncotarget, 9, 18269 (2018)
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Cohen SM, J. Pain Res., 5, 567 (2012)
Chahar P, Cummings KC, J. Pain Res., 5, 257 (2012)
Zimmermann M, Pain, 16, 109 (1983)
Kim SH, Chung JM, Pain, 50, 355 (1992)
Chaplan S, Bach F, Pogrel J, Chung J, Yaksh T, J. Neurosci. Methods, 53, 55 (1994)
Dixon WJ, Annu. Rev. Pharmacol. Toxicol., 20, 441 (1980)
Deuis JR, Dvorakova LS, Vetter I, Front. Mol. Neurosci., 10, 284 (2017)
Xu Q, Hashimoto M, Dang TT, Hoare T, Kohane DS, Whitesides GM, Langer R, Anderson DG, Small, 5, 1575 (2009)
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Yeo Y, Park K, Arch. Pharm. Res., 27, 1 (2004)
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[Referenced By]

[1] Apfelbaum JL, Chen C, Mehta SS, Gan TJ, Anesth. Analg., 97, 534 (2003)

[2] Chou R, Gordon DB, de Leon-Casasola OA, Rosenberg JM, Bickler S, Brennan T, Carter T, Cassidy CL, Chittenden EH, Degenhardt E, J. Pain, 17, 131 (2016)

[3] Kehlet H, Jensen TS, Woolf CJ, Lancet, 367, 1618 (2006)

[4] Rogers ML, Duffy JP, Eur. J. Cardiothorac. Surg., 18, 711 (2000)

[5] Perkins FM, Kehlet H, Anesthesiology, 93, 1123 (2000)

[6] Sihoe AD, Au SS, Cheung ML, Chow IK, Chu KM, Law CY, Wan M, Yim AP, Eur. J. Cardiothorac. Surg., 1054, 1054 (2004)

[7] Kandil E, Melikman E, Adinoff B, J. Anesth. Clin. Res., 8, 697 (2017)

[8] Wu CL, Cohen SR, Richman JM, Rowlingson AJ, Courpas GE, Cheung K, Lin EE, Liu SS, Anesthesiology, 103, 1079 (2005)

[9] Santamaria CM, Woodruff A, Yang R, Kohane DS, Mater. Today, 20, 22 (2017)

[10] Ekholm O, Kurita GP, Højsted J, Juel K, Sjøgren P, Pain, 155, 2486 (2014)

[11] Kuip EJ, Oldenmenger WH, Visser-Thijs MF, de Bruijn P, Oomen-de Hoop E, Mathijssen RH, Van der Rijt CC, Koolen SW, Oncotarget, 9, 18269 (2018)

[12] Møiniche S, Mikkelsen S, Wetterslev J, Dahl J, Br. J. Anaesth., 81, 377 (1998)

[13] Curley J, Castillo J, Hotz J, Uezono M, Hernandez S, Lim JO, Tigner J, Chasin M, Langer R, Berde C, Anesthesiology, 84, 1401 (1996)

[14] Mowat JJ, Mok MJ, MacLeod BA, Madden TD, Anesthesiology, 85, 635 (1996)

[15] Le Corre P, Estebe JP, Clement R, Du Plessis L, Chevanne F, Ecoffey C, Le Verge R, Int. J. Pharm., 238, 191 (2002)

[16] Grant GJ, Barenholz Y, Bolotin EM, Bansinath M, Turndorf H, Piskoun B, Davidson EM, Anesthesiology, 101, 133 (2004)

[17] Li H, Liu T, Zhu Y, Fu Q, Wu W, Deng J, Lan L, Shi S, Acta Biomater., 58, 136 (2017)

[18] Kim CM, Ullah A, Chang CH, Kim GM, Int. J. Precis. Eng. Manuf., 18, 599 (2017)

[19] Cohen SM, J. Pain Res., 5, 567 (2012)

[20] Chahar P, Cummings KC, J. Pain Res., 5, 257 (2012)

[21] Zimmermann M, Pain, 16, 109 (1983)

[22] Kim SH, Chung JM, Pain, 50, 355 (1992)

[23] Chaplan S, Bach F, Pogrel J, Chung J, Yaksh T, J. Neurosci. Methods, 53, 55 (1994)

[24] Dixon WJ, Annu. Rev. Pharmacol. Toxicol., 20, 441 (1980)

[25] Deuis JR, Dvorakova LS, Vetter I, Front. Mol. Neurosci., 10, 284 (2017)

[26] Xu Q, Hashimoto M, Dang TT, Hoare T, Kohane DS, Whitesides GM, Langer R, Anderson DG, Small, 5, 1575 (2009)

[27] Zhibo X, Miaobo Z, Aesthet. Surg. J., 29, 32 (2009)

[28] Kitajiri S, Tabuchi K, Hiraumi H, Kaetsu H, Laryngoscope, 111, 642 (2001)

[29] Patel VV, Zhao L, Wong P, Pradhan BB, Bae HW, Kanim L, Delamarter RB, Spine J., 6, 397 (2006)

[30] Patel VV, Zhao L, Wong P, Kanim L, Bae HW, Pradhan BB, Delamarter RB, Spine, 31, 1201 (2006)

[31] Kau YC, Liao CC, Chen YC, Liu SJ, Materials, 7, 6660 (2014)

[32] Yeo Y, Park K, Arch. Pharm. Res., 27, 1 (2004)

[33] Huang X, Brazel CS, J. Control. Release, 73, 121 (2001)

[34] Knudsen K, Suurkula MB, Blomberg S, Sjovall J, Edvardsson N, Br. J. Anaesth., 78, 507 (1997)

[35] Cox B, Durieux M, Marcus M, Best Pract. Res. Clin. Anaesthesiol., 17, 111 (2003)

[36] Das S, Bhattacharya P, Mandal MC, Mukhopadhyay S, Basu SR, Mando BKl, Indian J. Anaesth., 56, 27 (2012)

[37] Yamauchi Y, Isaka M, Ando K, Mori K, Kojima H, Maniwa T, Takahashi S, Ando E, Ohde Y, J. Cardiothorac. Surg., 12, 5 (2017)