Formulações de anestésicos locais de liberação controlada: aplicações terapêuticas

Daniele Ribeiro de Araújo; Luciana de Matos Alves Pinto; Angélica de Fátima de Assunção Braga; Eneida de Paula

doi:10.1590/S0034-70942003000500014

Miscellaneous

Formulações de anestésicos locais de liberação controlada: aplicações terapêuticas

Drug-delivery systems for local anesthetics: therapeutic applications

Daniele Ribeiro de Araújo; Luciana de Matos Alves Pinto; Angélica de Fátima de Assunção Braga; Eneida de Paula

http://dx.doi.org/10.1590/S0034-70942003000500014 Braz J Anesthesiol, vol.53, n5, p.663-671, 2003

PDF

Downloads: 0

Resumo

JUSTIFICATIVA E OBJETIVOS: O desenvolvimento de sistemas de liberação controlada tem sido alvo de pesquisas há pelo menos quatro décadas. Desde que foi sugerida sua aplicação na indústria farmacêutica, muitos resultados foram obtidos, especialmente na manipulação molecular de carreadores e no estudo de suas interações com as drogas encapsuladas. Esses novos carreadores têm a vantagem de contornar propriedades físico-químicas limitantes (como a solubilidade aquosa ou em membranas) das drogas encapsuladas, melhorando assim a farmacodinâmica (potencialização do efeito terapêutico), farmacocinética (controle da absorção e distribuição tecidual) e os efeitos toxicológicos (redução da toxicidade local e sistêmica) das mesmas. Entre os principais carreadores, destacam-se os lipossomas e as ciclodextrinas, que vêm trazendo inúmeras vantagens no desenvolvimento de formulações para liberação controlada de anestésicos locais. Este trabalho de revisão objetiva descrever a interação de anestésicos locais com lipossomas ou ciclodextrinas, o desenvolvimento das pesquisas básica e clínica nessa área, além da aplicabilidade terapêutica dessas formulações. CONTEÚDO: Lipossomas têm a capacidade de veicular drogas em órgãos-alvo, disponibilizando apenas uma fração - liberação controlada - para o sítio de ação. Já as ciclodextrinas alteram a intensidade e a duração do efeitos das drogas através da baixa absorção sistêmica do complexo. Pesquisas básicas e clínicas apontam como vantagens do uso de anestésicos locais encapsulados em lipossomas ou complexados com ciclodextrinas a liberação lenta da droga que prolonga a duração da anestesia e reduz a toxicidade para os sistemas cardiovascular e nervoso central. CONCLUSÕES: Embora várias pesquisas ainda estejam em andamento, os sistemas de liberação controlada de anestésicos locais indicam uma nova direção no desenvolvimento de formulações anestésicas mais eficazes e seguras.

Palavras-chave

ANESTÉSICOS

Abstract

BACKGROUND AND OBJECTIVES: Many researchers in the last four decades have been devoted to the development of drug-delivery systems. Since its first application in the pharmaceutical industry, many results have been obtained especially in the molecular manipulation of carriers and their interaction with encapsulated drugs. These new carriers have the advantage of bypassing encapsulated drugs restraining physicochemical properties (such as water or membrane solubility), thus improving pharmacodynamics (therapeutic effect potentiation), pharmacokinetics (control of tissue absorption and distribution) and toxic effects (lower local and systemic toxicity). Liposomes and cyclodextrins are among the most important carriers which have shown to be quite advantageous in the development of drug-delivery systems for local anesthetics. This study aimed at reviewing the interaction of local anesthetics with liposomes and cyclodextrins, the development of basic and applied research on the field, in addition to therapeutic applicability of these formulations. CONTENTS: Liposomes have the ability to control drug delivery to target tissues, fractionating drug release in its site of action. Cyclodextrins, on the other hand, change intensity and duration of effects due to low systemic drug absorption. Basic and clinical studies have pointed out that the administration of local anesthetics in liposome or cyclodextrin formulations induces slow release of the drugs, prolonging the anesthetic action and decreasing cardiac and nervous systems toxicity. CONCLUSIONS: Although studies are still in progress, drug-delivery systems are flagging a new direction for the development of safer and more effective local anesthetic formulations.

Keywords

ANESTHETICS

References

Siddall PJ, Cousins MJ. Pain mechanisms and management: an update. Clin Exp Pharmacol Physiol. 1995;22:679-688.

Bennett G, Deer T, Stuart DP. Future directions in the management of pain by intraspinal drug delivery. J Pain Symp Manag. 2000;20:44-50.

Åkerman B, Arweström E, Post C. Local anesthetics potentiate spinal morphine antinociception. Anesth Analg. 1988;67:943-948.

Whiteside JB, Wildsmith JAW. Developments in local anesthetics drugs. Br J Anaesth. 2001;87:27-35.

de Jong RH. Local Anesthetics. 1994:87-88.

Kuzma PJ, Kline MD, Calkins MD. Progress in the development of ultra-long-acting local anesthetics. Reg Anesth. 1997;22:543-551.

Ranade VV. Drug delivery systems. 1. Site-specific drug delivery using liposomes as carriers. J Clin Pharmacol. 1989;29:685-694.

Lichtenberg D, Barenholz Y. Liposomes: Preparation, characterization and preservation. Method Biochem Anal. 1988;33:337-462.

Grant GJ, Bansinath M. Liposomal delivery systems for local anesthetics. Reg Anesth Pain Med. 2001;26:61-63.

Sharata HH, Katz KH. Liposomes. Int J Dermatol. 1996;35:761-769.

Malinovsky J-M, Benhamou D, Alafandy M. Neurotoxicological assessment after intracisternal injection of liposomal bupivacaine in rabbits. Anesth Analg. 1997;85:1331-1336.

Rongen HAH, Bult A, van Bennekom WP. Liposomes and immunoassays. J Immunol Meth. 1997;204:105-133.

Law SL, Huang KJ, Chiang CH. Acyclovir-containing liposomes for potential ocular delivery corneal penetration and absorption. J Control Release. 2000;63:135-140.

Kotwani RN, Gokhale PC, Bodhe PV. A comparative study of plasma concentrations of liposomal amphotericin B (L-AMP-LRC-1) in adults, children and neonates. Int J Pharm. 2002;238:11-15.

Erridge C, Stewart J, Bennet-Guerrero . The biological activity of a liposomal complete core lipopolysacharide vaccine. J Endotoxin Res. 2002;8:39-46.

Stuart DD, Kao GY, Allen T. A novel long-circulating and functional liposomal formulation of antisense oligonucleotides targeted against MDR1. Cancer Gene Therapy. 2000;7:466-475.

Boogaerts J, Declercq A, Lafont N. Toxicity of bupivacaine encapsulated into liposomes and injected intravenously: comparision with plain solutions. Anesth Analg. 1993;76:553-555.

Boogaerts JG, Lafont ND, Luo HC. Plasma concentrations of bupivacaine after brachial plexus administration of liposome-associated and plain solutions to rabbits. Can J Anaesth. 1993;40:1201-1204.

Yu H-Y, Sun P, Hou W-Y. Prolonged local anesthetic effect of bupivacaine liposomes in rats. Int J Pharm. 1998;176:133-136.

Malinovsky JM, Bernard JM, Baudriment M. A chronic model for experimental investigation of epidural anesthesia in the rabbit. Reg Anesth. 1997;22:80-85.

Malinovsky JM, Le Corre P, Meunier JF. A dose-response study of liposomal bupivacaine in rabbits. J Contr Rel. 1999;60:111-119.

Boogaerts JG, Lafont ND, Declerq AG. Epidural administration of liposome-associated bupivacaine for the management of postsurgical pain: a first study. J Clin Anesth. 1994;6:315-320.

Lafont ND, Legros FJ, Boogaerts JG. Use of liposome-associated bupivacaine in a cancer pain syndrome. Anaesthesia. 1996;51:578-579.

Simonetti MPB, Andrade MP. Anestésicos locais e opióides encapsulados em lipossomas: um avanço farmacológico em progresso. Rev. Bras. Anestesiol. 1996;46:35-42.

Langerman L, Grant GJ, Zakowski M. Prolongation of epidural anesthesia using a lipid carrier with procaine, lidocaine and tetracaine. Anesth Analg. 1992;75:900-905.

Mowat JJ, Mok MJ, MacLeod BA. Liposomal bupivacaine. Anesthesiol. 1996;85:635-643.

Loftsson T, Masson M. Cyclodextrins in topical drug formulations: theory and practice. Int J Pharm. 2001;225:15-30.

Matioli G. Ciclodextrinas e suas aplicações em alimentos, fármacos, agricultura, biotecnologia, química analítica e produtos gerais. 2000:3-5.

McCormack B, Gregoriadis G. Drugs-in-cyclodextrins-in-liposomes: an approach to controlling the fate of water insoluble drugs in vivo. Int J Pharmac. 1998;162:59-69.

Bibby D, Davies NM, Tucker IG. Mechanisms by wich cyclodextrins modify drug release from polymeric drug delivery systems. Int J Pharmac. 2000;197:1-11.

Kalinkova GN. Studies of beneficial interactions between active medicaments and excipients in pharmaceutical formulations. Int J Pharm. 1999;187:1-15.

Frömming K-H, Szejtli J. Topics in Inclusion Science: Cyclodextrins in Pharmacy. 1994:50-51.

Kirchmeier MJ, Ishida T, Chevrette J. Correlations between the rate of intracellular release of endocytosed liposomal doxorubicin and cytotoxicity as determined by a new assay. J Liposome Res. 2001;11:15-29.

Veiga F, Fernandes C, Teixeira F. Oral availability and hypoglycaemic activity of tolbutamide/cyclodextrin inclusion complexes. Int J Pharm. 2000;202:165-171.

Dalmora ME, Dalmora SL, Oliveira AG. Inclusion complex of piroxicam withbeta-cyclodextrin and incorporation in cationic microemulsion: In vitro drug release and in vivo topical anti-inflammatory effect. Int J Pharm. 2001;222:45-55.

Irie T, Uekama K. Pharmaceutical applications of ciclodextrins.: III.Toxicological issues and safety evaluation. J Pharm Sci. 1997;86:147-162.

Rajewski RA, Stella VJ. Pharmaceutical applications of cyclodextrins: 2.In vivo Drug delivery. J Pharm Sci. 1996;85:1142-1169.

Dollo G, Le Corre P, Chevanne F. Inclusion complexation of amide-type local anesthetics with beta-cyclodextrin and derivates: I.Physicochemical characterization. Int J Pharmac. 1996;131:219-228.

Dollo G, Le Corre P, Chevanne F. Inclusion complexation of amide-type local anesthetics with beta-cyclodextrin and derivates: Evaluation of affinity constants and in vitro transfer rate constants. Int J Pharmac. 1996;136:165-174.

Fréville JC, Dollo G, Le Corre P. Controlled systemic absorption and increased anesthetic effect of bupivacaine following epidural administration of bupivacaine-hydroxypropyl-beta-cyclodextrin complex. Pharm Res. 1996;13:1576-1580.

Dollo G, Thompson DO, Le Corre P. Inclusion complexation of amide-type local anesthetics with beta-cyclodextrin and derivates: III. Biopharmaceutics of bupivacaine-SBE7-beta-ciclodextrina complex following percutaneous sciatic nerve administration in rabbits. Int J Pharmac. 1998;164:11-19.

Dollo G, Le Corre P, Freville JC. Biopharmaceutics of local anesthetic cyclodextrin complexes following loco-regional administration. Ann Pharm Fr. 2000;58:425-432.

Fletcher D, Le Corre P, Guilbaud G. Antinociceptive effect of bupivacaine encapsulated in poly(D,L)-lactide-co-glycolide microspheres in the acute inflammatory pain model of carrageenin-injected rats. Anesth Analg. 1997;84:90-94.

Garry MG, Jackson DL, Geier HE. Evaluation of the efficacy of a bupivacaine polymer system on nociception and inflammatory mediator release. Pain. 1999;82:49-55.

Kohane DS, Lipp M, Kinney RC. Sciatic nerve blockade with lipid-protein-sugar particles containing bupivacaine. Pharm Res. 2000;17:1243-1249.

Grant GJ, Barenholz Y, Piskoun B. DRV liposomal bupivacaine: preparation, characterization and in vivo evaluation in mice. Pharm Res. 2001;18:336-343.

Formulações de anestésicos locais de liberação controlada: aplicações terapêuticas

Drug-delivery systems for local anesthetics: therapeutic applications

Daniele Ribeiro de Araújo; Luciana de Matos Alves Pinto; Angélica de Fátima de Assunção Braga; Eneida de Paula

Resumo

Palavras-chave

Abstract

Keywords

References

Links

Share

Braz J Anesthesiol