Generic placeholder image

Current Drug Delivery

Author(s): Xiqing Zhao, Yue Gao, Xuemei Tang, Wei Lei, Yang Yang, Fanglin Yu, Yan Liu, Meiyan Yang, Yuli Wang, Wei Gong, Zhiping Li*, ChunSheng Gao* and Xingguo Mei

DOI: 10.2174/1567201816666190528122137

DownloadDownload PDF Flyer Cite As
Development and Evaluation of Ropivacaine Loaded Poly(Lactic-Co-Glycolic Acid) Microspheres with Low Burst Release

Page: [490 - 499] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Background: The local anesthetic drugs, especially ropivacaine, were considered favorable analgesia for postoperative management because of their effective local pain relief and low adverse effects. However, the short half-life and the resulting in bolus doses lead to the indistinctive improvement of these drugs in postoperative pain relief. Therefore, the ropivacaine microspheres with sustained release and low initial burst release were anticipated.

Methods: Three methods including oil in water (O/W), water in oil in water (W/O/W), and solid in oil in water (S/O/W) emulsion solvent evaporation method were used to optimize the ropivacaine loaded PLGA microspheres. The microspheres were evaluated both in vitro and in rats. The in vitro-in vivo correlation (IVIVC) was also investigated.

Results: The microspheres prepared by O/W method showed more satisfactory properties and the microspheres used for evaluation were prepared by O/W method. The particle size, drug loading, encapsulation efficiency and burst release were 11.19±1.24 µm, 28.37±1.15%, 98.15±3.98%, and 10.96±5.37% for microspheres with PLGA of 12 kDa, and 6.64±0.61 μm, 19.62±0.89%, 92.74±4.21%, and 18.42±5.12% for microspheres with PLGA of 8 kDa, respectively. These microspheres were also injected into rats by subcutaneous, intramuscular and intraperitoneal route, respectively. It was indicated that the detectable concentration of ropivacaine could last for at least 20 days for both kinds of microspheres in spite of injection routes. The low burst releases at 1 d were also manifested in rats and they were 6.62%, 6.99%, 6.48% for the microspheres with PLGA of 12 kDa, and 4.72%, 4.33%, 4.48% for the microspheres with PLGA of 8 kDa by intraperitoneal, intramuscular and subcutaneous route, respectively. A linear relationship between the in vitro release and the in vivo adsorption of ropivacaine from microspheres was also established.

Conclusion: The ropivacaine microspheres with sustained release and low burst release were acquired, which indicated that the postoperative pain relief might last longer and the side effects might get lower. Therefore, the ropivacaine microspheres prepared in this paper have great potential for clinical use.

Keywords: Microspheres, ropivacaine, pharmacokinetic, sustained release effect, initial burst release, IVIVC.

Graphical Abstract

[1]
Sharrock, N.E.; Cazan, M.G.; Hargett, M.J.; Williams-Russo, P.; Wilson, P.D., Jr Changes in mortality after total hip and knee arthroplasty over a ten-year period. Anesth. Analg., 1995, 80(2), 242-248. [http://dx.doi.org/10.1097/00000539-199502000-00008]. [PMID: 7818108].
[2]
Dhanapal, B.; Sistla, S.C.; Badhe, A.S.; Ali, S.M.; Ravichandran, N.T.; Galidevara, I. Effectiveness of continuous wound infusion of local anesthetics after abdominal surgeries. J. Surg. Res., 2017, 212, 94-100. [http://dx.doi.org/10.1016/j.jss.2016.12.027]. [PMID: 28550928].
[3]
Santamaria, C.M.; Woodruff, A.; Yang, R.; Kohane, D.S. Drug delivery systems for prolonged duration local anesthesia. Mater Today (Kidlington), 2017, 20(1), 22-31. [http://dx.doi.org/10.1016/j.mattod.2016.11.019]. [PMID: 28970739].
[4]
Kristensen, B.B.; Christensen, D.S.; Østergaard, M.; Skjelsager, K.; Nielsen, D.; Mogensen, T.S. Lack of postoperative pain relief after hysterectomy using preperitoneally administered bupivacaine. Reg. Anesth. Pain Med., 1999, 24(6), 576-580. [http://dx.doi.org/10.1097/00115550-199924060-00018]. [PMID: 10588565].
[5]
Ma, P.; Li, T.; Xing, H.; Wang, S.; Sun, Y.; Sheng, X.; Wang, K. Local anesthetic effects of bupivacaine loaded lipid-polymer hybrid nanoparticles: In vitro and in vivo evaluation. Biomed. Pharmacother., 2017, 89, 689-695. [http://dx.doi.org/10.1016/j.biopha.2017.01.175]. [PMID: 28267672].
[6]
Xu, B.; Ren, L.; Tu, W.; Wu, Z.; Ai, F.; Zhou, D.; Chen, B.; Zhang, X. Continuous wound infusion of ropivacaine for the control of pain after thoracolumbar spinal surgery: A randomized clinical trial. Eur. Spine J., 2017, 26(3), 825-831. [http://dx.doi.org/10.1007/s00586-015-3979-x]. [PMID: 25935145].
[7]
Liu, F.F.; Liu, X.M.; Liu, X.Y.; Tang, J.; Jin, L.; Li, W.Y.; Zhang, L.D. Postoperative continuous wound infusion of ropivacaine has comparable analgesic effects and fewer complications as compared to traditional patient-controlled analgesia with sufentanil in patients undergoing non-cardiac thoracotomy. Int. J. Clin. Exp. Med., 2015, 8(4), 5438-5445. [PMID: 26131121].
[8]
Shichor, I.; Shomron, N.; Lawlor, M.W.; Bae, S.A.; Zoldan, J.; Langer, R.; Kohane, D.S. Toxicogenomic analysis of a sustained release local anesthetic delivery system. Biomaterials, 2012, 33(13), 3586-3593. [http://dx.doi.org/10.1016/j.biomaterials.2012.01.043]. [PMID: 22341215].
[9]
Ohri, R.; Wang, J.C.; Blaskovich, P.D.; Pham, L.N.; Costa, D.S.; Nichols, G.A.; Hildebrand, W.P.; Scarborough, N.L.; Herman, C.J.; Strichartz, G.R. Inhibition by local bupivacaine-releasing microspheres of acute postoperative pain from hairy skin incision. Anesth. Analg., 2013, 117(3), 717-730. [http://dx.doi.org/10.1213/ANE.0b013e3182a00851]. [PMID: 23921651].
[10]
Epstein-Barash, H.; Shichor, I.; Kwon, A.H.; Hall, S.; Lawlor, M.W.; Langer, R.; Kohane, D.S.; Meinwald, J. Prolonged duration local anesthesia with minimal toxicity. Proc. Natl. Acad. Sci. USA, 2009, 106(17), 7125-7130. [http://dx.doi.org/10.1073/pnas.0900598106]. [PMID: 19365067].
[11]
Masters, D.B.; Domb, A.J. Liposphere local anesthetic timed-release for perineural site application. Pharm. Res., 1998, 15(7), 1038-1045. [http://dx.doi.org/10.1023/A:1011978010724]. [PMID: 9688057].
[12]
Karashima, K.; Taniguchi, M.; Nakamura, T.; Takasaki, M.; Matsuo, K.; Irikura, M.; Irie, T. Prolongation of intrathecal and sciatic nerve blocks using a complex of levobupivacaine with maltosyl-beta-cyclodextrin in rats. Anesth. Analg., 2007, 104(5), 1121-1128. [http://dx.doi.org/10.1213/01.ane.0000260309.15034.52]. [PMID: 17456662].
[13]
Hoare, T.; Bellas, E.; Zurakowski, D.; Kohane, D.S. Rheological blends for drug delivery. II. Prolongation of nerve blockade, biocompatibility, and in vitro-in vivo correlations. J. Biomed. Mater. Res. A, 2010, 92(2), 586-595. [http://dx.doi.org/10.1002/jbm.a.32420]. [PMID: 19280629].
[14]
Jia, X.; Colombo, G.; Padera, R.; Langer, R.; Kohane, D.S. Prolongation of sciatic nerve blockade by in situ cross-linked hyaluronic acid. Biomaterials, 2004, 25(19), 4797-4804. [http://dx.doi.org/10.1016/j.biomaterials.2003.12.012]. [PMID: 15120526].
[15]
Rwei, A.Y.; Lee, J.J.; Zhan, C.; Liu, Q.; Ok, M.T.; Shankarappa, S.A.; Langer, R.; Kohane, D.S. Repeatable and adjustable on-demand sciatic nerve block with phototriggerable liposomes. Proc. Natl. Acad. Sci. USA, 2015, 112(51), 15719-15724. [http://dx.doi.org/10.1073/pnas.1518791112]. [PMID: 26644576].
[16]
Hoare, T.; Santamaria, J.; Goya, G.F.; Irusta, S.; Lin, D.; Lau, S.; Padera, R.; Langer, R.; Kohane, D.S. A magnetically triggered composite membrane for on-demand drug delivery. Nano Lett., 2009, 9(10), 3651-3657. [http://dx.doi.org/10.1021/nl9018935]. [PMID: 19736912].
[17]
Masters, D.B.; Berde, C.B.; Dutta, S.; Turek, T.; Langer, R. Sustained local anesthetic release from bioerodible polymer matrices: A potential method for prolonged regional anesthesia. Pharm. Res., 1993, 10(10), 1527-1532. [http://dx.doi.org/10.1023/A:1018995913972]. [PMID: 8272418].
[18]
Weldon, C.B.; Tsui, J.H.; Shankarappa, S.A.; Nguyen, V.T.; Ma, M.; Anderson, D.G.; Kohane, D.S. Electrospun drug-eluting sutures for local anesthesia. J. Control. Release, 2012, 161(3), 903-909. [http://dx.doi.org/10.1016/j.jconrel.2012.05.021]. [PMID: 22609349].
[19]
Chen, P.C.; Kohane, D.S.; Park, Y.J.; Bartlett, R.H.; Langer, R.; Yang, V.C. Injectable microparticle-gel system for prolonged and localized lidocaine release. II. In vivo anesthetic effects. J. Biomed. Mater. Res. A, 2004, 70(3), 459-466. [http://dx.doi.org/10.1002/jbm.a.30101]. [PMID: 15293320].
[20]
Cohen, R.; Kanaan, H.; Grant, G.J.; Barenholz, Y. Prolonged analgesia from Bupisome and Bupigel formulations: From design and fabrication to improved stability. J. Control. Release, 2012, 160(2), 346-352. [http://dx.doi.org/10.1016/j.jconrel.2011.12.030]. [PMID: 22233969].
[21]
Le Corre, P.; Estèbe, J.P.; Clément, R.; Du Plessis, L.; Chevanne, F.; Ecoffey, C.; Le Verge, R. Spray-dryed bupivacaine-loaded microspheres: In vitro evaluation and biopharmaceutics of bupivacaine following brachial plexus administration in sheep. Int. J. Pharm., 2002, 238(1-2), 191-203. [http://dx.doi.org/10.1016/S0378-5173(02)00067-4]. [PMID: 11996823].
[22]
Suto, T.; Obata, H.; Tobe, M.; Oku, H.; Yokoo, H.; Nakazato, Y.; Saito, S. Long-term effect of epidural injection with sustained-release lidocaine particles in a rat model of postoperative pain. Br. J. Anaesth., 2012, 109(6), 957-967. [http://dx.doi.org/10.1093/bja/aes302]. [PMID: 22923636].
[23]
Kang, D.K.; Zhao, L.Y.; Wang, H.L. Cytotoxic effects of local anesthesia through lidocaine/ropivacaine on human melanoma cell lines. Rev. Bras. Anestesiol., 2016, 66(6), 594-602. [http://dx.doi.org/10.1016/j.bjan.2016.08.002]. [PMID: 27639508].
[24]
Budharapu, A.; Sinha, R.; Uppada, U.K.; Subramanya Kumar, A.V. Ropivacaine: a new local anaesthetic agent in maxillofacial surgery. Br. J. Oral Maxillofac. Surg., 2015, 53(5), 451-454. [http://dx.doi.org/10.1016/j.bjoms.2015.02.021]. [PMID: 25818492].
[25]
Qin, W.W.; Jiao, Z.; Zhong, M.K.; Shi, X.J.; Zhang, J.; Li, Z.D.; Cui, X.Y. Simultaneous determination of procaine, lidocaine, ropivacaine, tetracaine and bupivacaine in human plasma by high-performance liquid chromatography. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2010, 878(15-16), 1185-1189. [http://dx.doi.org/10.1016/j.jchromb.2010.03.003]. [PMID: 20356808].
[26]
Affas, F.; Stiller, C.O.; Nygårds, E.B.; Stephanson, N.; Wretenberg, P.; Olofsson, C. A randomized study comparing plasma concentration of ropivacaine after local infiltration analgesia and femoral block in primary total knee arthroplasty. Scand. J. Pain, 2012, 3(1), 46-51. [http://dx.doi.org/10.1016/j.sjpain.2011.09.001]. [PMID: 29913764].
[27]
Hu, X.; Zhang, J.; Tang, X.; Li, M.; Ma, S.; Liu, C.; Gao, Y.; Zhang, Y.; Liu, Y.; Yu, F.; Yang, Y.; Guo, J.; Li, Z.; Mei, X. An accelerated release method of risperidone loaded plga microspheres with good IVIVC. Curr. Drug Deliv., 2018, 15(1), 87-96. [http://dx.doi.org/10.2174/1567201814666170516113406]. [PMID: 28521697].
[28]
Li, Z.; Li, L.; Liu, Y.; Zhang, H.; Li, X.; Luo, F.; Mei, X. Development of interferon alpha-2b microspheres with constant release. Int. J. Pharm., 2011, 410(1-2), 48-53. [http://dx.doi.org/10.1016/j.ijpharm.2011.03.016]. [PMID: 21419205].
[29]
Su, Z.; Sun, F.; Shi, Y.; Jiang, C.; Meng, Q.; Teng, L.; Li, Y. Effects of formulation parameters on encapsulation efficiency and release behavior of risperidone poly(D,L-lactide-co-glycolide) microsphere. Chem. Pharm. Bull. (Tokyo), 2009, 57(11), 1251-1256. [http://dx.doi.org/10.1248/cpb.57.1251]. [PMID: 19881277].
[30]
Gaignaux, A.; Réeff, J.; Siepmann, F.; Siepmann, J.; De Vriese, C.; Goole, J.; Amighi, K. Development and evaluation of sustained-release clonidine-loaded PLGA microparticles. Int. J. Pharm., 2012, 437(1-2), 20-28. [http://dx.doi.org/10.1016/j.ijpharm.2012.08.006]. [PMID: 22903047].
[31]
Costa, P.; Sousa, Lobo J.M. Modeling and comparison of dissolution profiles. Eur. J. Pharm. Sci., 2001, 13(2), 123-133. [http://dx.doi.org/10.1016/S0928-0987(01)00095-1]. [PMID: 11297896].
[32]
Xie, X.; Li, Z.; Zhang, L.; Chi, Q.; Yang, Y.; Zhang, H.; Yang, Y.; Mei, X. A novel accelerated in vitro release method to evaluate the release of thymopentin from PLGA microspheres. Pharm. Dev. Technol., 2015, 20(5), 633-640. [http://dx.doi.org/10.3109/10837450.2014.892131]. [PMID: 24597702].
[33]
Chu, D.F.; Fu, X.Q.; Liu, W.H.; Liu, K.; Li, Y.X. Pharmacokinetics and in vitro and in vivo correlation of huperzine A loaded poly(lactic-co-glycolic acid) microspheres in dogs. Int. J. Pharm., 2006, 325(1-2), 116-123. [http://dx.doi.org/10.1016/j.ijpharm.2006.06.032]. [PMID: 16876971].
[34]
Li, Z.; Yu, F.; Di, Z.; Zhao, X.; Zhao, S.; Liu, Y.; Li, Y.; Wang, Z.; Gong, W.; Zhang, H.; Yang, Y.; Xie, X.; Mei, X. Development and uniform evaluation of ropinirole osmotic pump tablets with REQUIP XL both in vitro and in beagle dogs. Drug Dev. Ind. Pharm., 2016, 42(1), 12-18. [http://dx.doi.org/10.3109/03639045.2015.1020219]. [PMID: 25830369].
[35]
Zuidema, J.; Pieters, F.A.J.M.; Duchateau, G.S.M.J.E.; Zuidema, J.; Pieters, F.A.J.M.; Duchateau, G.S.M.J.E. Release and absorption rate aspects of intramuscularly injected pharmaceuticals. Int. J. Pharm., 1988, 47(1), 1-12. [http://dx.doi.org/10.1016/0378-5173(88)90209-8].
[36]
Vaag, A.; Handberg, A.; Lauritzen, M.; Henriksen, J.E.; Pedersen, K.D.; Beck-Nielsen, H. Variation in absorption of NPH insulin due to intramuscular injection. Diabetes Care, 1990, 13(1), 74-76. [http://dx.doi.org/10.2337/diacare.13.1.74]. [PMID: 2404719].
[37]
Tassi, P.; Ormas, P.; Madonna, M.; Carli, S.; Belloli, C.; De Natale, G.; Ceci, L.; Marcotrigiano, G.O. Pharmacokinetics of N-methyl-glucamine antimoniate after intravenous, intramuscular and subcutaneous administration in the dog. Res. Vet. Sci., 1994, 56(2), 144-150. [http://dx.doi.org/10.1016/0034-5288(94)90096-5]. [PMID: 8191002].
[38]
Ranheim, B.; Ween, H.; Egeli, A.K.; Hormazabal, V.; Yndestad, M.; Søli, N.E. Benzathine penicillin G and procaine penicillin G in piglets: Comparison of intramuscular and subcutaneous injection. Vet. Res. Commun., 2002, 26(6), 459-465. [http://dx.doi.org/10.1023/A:1020590408947]. [PMID: 12241099].