1. School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China; 2. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China
Abstract：Patients require proper pain relief after surgery. Local anesthetics are widely used to control postoperative pain, but their clinical application is limited due to short duration of action. In decades of research, the long-acting delivery systems have been applied to local anesthetics, with the purpose of locally and continuously release drugs to prolong the action of drugs and reduce the side effects. The study of local anesthetics long-acting delivery systems has laid foundation for clinical postoperative analgesia.This paper reviewed the research status of long-acting drug delivery systems for local anesthetics, and discussed the advantages and existing problems.
陈茹莹, 徐晖, 邢金锋, 魏振平. 局部麻醉药长效递送系统的开发及其在术后镇痛中的应用进展[J]. 中国药学杂志, 2020, 55(9): 709-714.
CHEN Ru-ying, XU Hui, XING Jin-feng, WEI Zhen-ping. Progress in Development of Long-acting Delivery Systems for Local Anesthetics and Its Application in Postoperative Analgesia. Chinese Pharmaceutical Journal, 2020, 55(9): 709-714.
LOVICHSAPOLA J, SMITH C E, BRANDT C P. Postoperative pain control [J]. Surg Clin North Am, 2015, 95(2):301-318.
[2]
BEVERLY A, KAYE A D, LJUNGQVIST O, et al. Essential elements of multimodal analgesia in enhanced recovery after surgery (ERAS) guidelines [J]. Anesthesiol Clin, 2017, 35(2):e115-e143.
[3]
GOLEMBIEWSKI J, DASTA J. Evolving role of local anesthetics in managing postsurgical analgesia [J]. Clin Ther, 2015, 37(6):1354-1371.
[4]
JOSE A, MORAL A D, COBO I, et al. The role of continuous peripheral nerve blocks [J]. Anesthesiol Res Pract, 2012, 2012:560879.
[5]
YIN Q Q, ZHANG W S. Research advance in long-lasting local anesthetics [J]. Prog Pharm Sci(药学进展), 2017, 41(8):574-578.
[6]
ZORZETTO L, BRAMBILLA P, MARCELLO E, et al. From micro-to nanostructured implantable devicefor local anesthetic delivery [J]. Int J Nanomed, 2016, 11:2695-2709.
[7]
KAU Y C, LIAO C C, CHEN Y C, et al. Sustained release of lidocaine from solvent-free biodegradable poly[(d,l)-lactide-co-glycolide] (PLGA):in vitro and in vivo study [J]. Materials(Basel), 2014, 7(9):6660-6676.
[8]
LIU J, LV X.The pharmacokinetics and pharmacodynamics of lidocaine-loaded biodegradable poly(lactic-co-glycolic acid) microspheres [J]. Int J Mol Sci, 2014, 15(10):17469-17477.
[9]
GOLOVANEVSKI L, ICKOWICZ, SOKOLSKY P M. In vivo study of an extended release bupivacaine formulation following site-directed nerve injection [J]. J Bioact Compat Polym, 2015, 30(1):114-125.
[10]
AHMED T. Review:approaches to develop PLGA based in situ gelling system with low initial burst [J]. Pak J Pharm Sci, 2015, 28(2):657-665.
[11]
KIRKSEY M A, HASKINS S C, CHENG J, et al. Local anesthetic peripheral nerve block adjuvants for prolongation of analgesia: a systematic qualitative review [J]. PLoS One, 2015, 10 (9):e0137312.
[12]
SINGH N, TIWARI A, KESHARWANI R, et al. Pharmaceutical polymer in drug delivery: a review [J]. Res J Pharm Technol, 2016, 9(7):982-994.
[13]
MYERS M, REGINALD P W . A drug delivery device for providing local analgesia, local anesthesia ornerve blockade:US, 692337 [P]. 2016-10-26.
[14]
NASKAR S, KOUTSU K, SHARMA S. Chitosan-based nanoparticles as drug delivery systems: a review on two decades of research [J]. J Drug Target, 2019,27(4):379-393.
[15]
PASTORINO L, DELLACASA E, PETRINI P, et al. Stereocomplex poly(lactic acid) nanocoated chitosan microparticles for the sustained release of hydrophilic drugs [J]. Mater Sci Eng C Mater Biol Appl, 2017, 76:1129-1135.
[16]
XU Y, KIM C S, SAYLOR D M, et al. Polymer degradation and drug delivery in PLGA-based drug-polymer applications: a review of experiments and theories [J]. J Biomed Mater Res B Appl Biomater, 2017,105(6):1692-1716.
[17]
YUAN J J, XIE Y Z. Study on methods of drug loading into delivery carriers [J]. Chin Bull Life Sci(生命科学), 2013, 25(3):329-333.
[18]
TOBE M, OBATA H, SUTO T, et al. Long-term effect of sciatic nerve block with slow-release lidocaine in a rat model of postoperative pain [J]. Anesthesiology, 2010, 112 (6):1473-1481.
[19]
SVIRSKIS D, CHANDRAMOULI K, BHUSAL P, et al. Injectable thermosensitive gelling delivery system for the sustained release of lidocaine [J]. Ther Deliv, 2016, 7(6):359-368.
[20]
PEK Y S, PITUKMANOROM P, YING J Y. Sustained release of bupivacaine for post-surgical pain relief using core-shell microspheres [J]. J Mater Chem B, 2014, 2(46):8194-8200.
[21]
VYAS K S, RAJENDRAN S, MORRISON S D, et al. Systematic review of liposomal bupivacaine (Exparel®) for postoperative analgesia [J]. Plast Reconstr Surg, 2016, 138(4):748e-756e.
[22]
KEMPE S, MADER K. In situ forming implants-an attractive formulation principle for parenteral depot formulations [J]. J Controlled Release, 2012, 161(2):668-679.
[23]
ZHAO Y, ZHOU L, LIU J, et al. Preparation and investigation of a novel levobupivacaine implant gel for prolonged local anesthetics [J]. Artif Cells Nanomed Biotechnol, 2017, 45(3):404-408.
[24]
NI Q, CHEN W, TONG L, et al. Preparation of novel biodegradable ropivacaine microspheres and evaluation of their efficacy in sciatic nerve block in mice [J]. Drug Des Devel Ther, 2016, 10:2499-2506.
[25]
LU L, ZHANG W, WU X, et al. A novel ropivacaine-loaded in situ forming implant prolongs the effect of local analgesia in rats [J]. Arch Med Sci, 2013,9(4):614-621.
[26]
WANG C F, DJALALI A G, GANDHI A, et al. An absorbable local anesthetic matrix provides several days of functional sciatic nerve blockade [J]. Anesth Analg, 2009, 108(3):1027-1033.
[27]
CUSACK S L, HEMSEN L, REGINALD P, et al. The pharmacokinetics and safety of an intraoperative bupivacaine-collagen implant (XaraColl®) for postoperative analgesia in women following total abdominal hysterectomy [J]. J Pain Res, 2013, 6:151-159.
[28]
HAN F Y, THURECHT K J, WHITTAKER A K, et al. Bioerodable PLGA-based microparticles for producing sustained-release drug formulations and strategies for improving drug loading [J]. Front Pharmacol, 2016, 7:185.
[29]
SHEPHERD S D, O'BUCKLEY S C, HARRINGTON J M, et al. A moldable sustained release bupivacaine formulation for tailored treatment of postoperative dental pain [J]. Sci Rep, 2018, 8(1):12172.
[30]
MORE R K, SONAWANE D S, PATIL M P, et al. An overview: use of polymer microspheres in controlled drug delivery [J]. Res J Pharm Dosage Forms Technol, 2018, 10(3):193-199.
[31]
KIM C M, ULLAH A, CHANG C H, et al. Preparation of lidocaine-loaded porous poly (lactic-co-glycolic acid) microparticles using microfluidic flow focusing and phosphate buffer solution porogen [J]. Int J Precis Eng Man, 2017, 18 (4):599-604.
[32]
LAMBRECHTS M, O'BRIEN M J, SAVOIE F H, et al. Liposomal extended-release bupivacaine for postsurgical analgesia [J]. Patient Prefer Adherence, 2013, 7:885-890.
[33]
VANDEPITTE C, KURODA M, WITVROUW R, et al. Addition of liposome bupivacaine to bupivacaine HCl versus bupivacaine HCl alone for interscalene brachial plexus block in patients having major shoulder surgery [J]. Reg Anesth Pain Med, 2017, 42(3):334-341.
[34]
BURBRIDGE M, JAFFE R A. Exparel®: a new local anesthetic with special safety concerns [J]. Anesth Analg, 2015, 121 (4):1113-1114.
[35]
THAKUR R R, MCMILLAN H L, JONES D S. Solvent induced phase inversion-based in situ forming controlled release drug delivery implants [J]. J Controlled Release, 2014, 176:8-23.
[36]
GANDHI A, PAUL A, SEN S O, et al. Studies on thermoresponsive polymers: phase behaviour, drug delivery and biomedical applications [J]. Asian J Pharm Sci, 2015, 10(2):99-107.
[37]
WEI G, XU H, ZHENG J M. Formation mechanism of in situ gel and its application in drug controlled release [J]. Chin Pharm J(中国药学杂志), 2003, 38(8):564-568.
[38]
DUMORTIER G, GROSSIORD J L, AGNELY F, et al. A review of poloxamer 407 pharmaceutical and pharmacological characteristics [J]. Pharm Res, 2006, 23 (12):2709-2728.
[39]
SVIRSKIS D, CHANDRAMOULI K, BHUSAL P, et al. Injectable thermosensitive gelling delivery system for the sustained release of lidocaine [J]. Ther Deliv, 2016, 7 (6):359-368.
[40]
FU X, ZENG H, GUO J, et al. A PLGA-PEG-PLGA thermosensitive gel enabling sustained delivery of ropivacaine hydrochloride for postoperative pain relief [J]. Chem Pharm Bull (Tokyo), 2017, 65(3):229-235.
[41]
BONACUCINA G, CESPI M, MENCARELLI G, et al. Thermosensitive self-assembling block copolymers as drug delivery systems [J]. Polymers, 2011, 3 (2):779.
[42]
GENG Z, LUO X, ZHANG Z, et al. Study of an injectable in situ forming gel for sustained-release of ivermectin in vitro and in vivo [J]. Int J Biol Macromol, 2016, 85:271-276.
[43]
PORTILLO J, KAMAR N, MELIBARY S, et al. Safety of liposome extended-release bupivacaine for postoperative pain control [J]. Front Pharmacol, 2014, 5:90.
[44]
YAPAR E A, ZKAN Y, BAYKARA T. Injectable in situ forming microparticles: a novel drug delivery system [J]. Trop J Pharm Res, 2012, 11(2):307-318.
[45]
KRANZ H, YILMAZ E, BRAZEAU G A, et al. In vitro and in vivo drug release from a novel in situ forming drug delivery system [J]. Pharm Res, 2008, 25 (6):1347-1354.
[46]
CHEN P C, KOHANE D S, PARK Y J, et al. Injectable microparticle-gel system for prolonged and localized lidocaine release. Ⅱ. In vivo anesthetic effects [J]. J Biomed Mater Res A,2004,70(3):459-466.
[47]
YIN Q Q, WU L, GOU M L, et al. Long-lasting infiltration anaesthesia by lidocaine-loaded biodegradable nanoparticles in hydrogel in rats [J]. Acta Anaesthesiol Scand, 2009, 53 (9):1207-1213.
[48]
LI H, LIU T, ZHU Y, et al. An in situ-forming phospholipid-based phase transition gel prolongs the duration of local anesthesia for ropivacaine with minimal toxicity [J]. Acta Biomater, 2017, 58:136-145.
[49]
DINH V V, SUH Y S, YANG H K, et al. Spatiotemporal programing for the on-demand release of bupivacaine based on an injectable composite hydrogel [J]. J Pharm Sci, 2016, 105(12):3634-3644.
[50]
LEIMAN D, MINKOWITZ H S, PATEL S S, et al. Reduced pain intensity and opioid consumption for 96 hours after abdominoplasty after administration of HTX-011, a proprietary, extended-release combination of bupivacaine and meloxicam [J]. J Am Coll Surgeons, 2017, 225(4):e147.
[51]
BALOCCO A L, VAN ZUNDERT P G E, GAN S S, et al. Extended release bupivacaine formulations for postoperative analgesia [J]. Curr Opin Anaesthesiol, 2018,31(5):636-642.
2020, Vol. 55 
