Physico-chemical characterization of inclusion complex between hydroxymethylnitrofurazone and hydroxypropyl-beta-cyclodextrin

Hydroxymethylnitrofurazone (NFOH) is a prodrug that is active against Trypanosoma cruzi. It however presents low solubility and high toxicity. Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) can be used as a drug-delivery system for NFOH modifying its physico-chemical properties. The aim of this work is to characterize the inclusion complex between NFOH and HP-beta-CD. The rate of NFOH release decreases after complexation and thermodynamic parameters from the solubility isotherm studies revealed that a stable complex is formed (deltaGº= 1.7 kJ/mol). This study focuses on the physico-chemical characterization of a drug-delivery formulation that comes out as a potentially new therapeutic option for Chagas disease treatment.FAPESPCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES

Physico-chemical characterization of inclusion complex between hydroxymethylnitrofurazone and hydroxypropyl-b-cyclodextrin

Hydroxymethylnitrofurazone (NFOH) is a prodrug that is active against Trypanosoma cruzi. It however presents low solubility and high toxicity. Hydroxypropyl-b-cyclodextrin (HP-b-CD) can be used as a drug-delivery system for NFOH modifying its physico-chemical properties. The aim of this work is to characterize the inclusion complex between NFOH and HP-b-CD. The rate of NFOH release decreases after complexation and thermodynamic parameters from the solubility isotherm studies revealed that a stable complex is formed (DGº= 1.7 kJ/mol). This study focuses on the physico-chemical characterization of a drug-delivery formulation that comes out as a potentially new therapeutic option for Chagas disease treatment312290295COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP00019-08-0305/03045-9; 04/02091-4; 06/00787-

Drug-delivery Systems For Racemic Bupivacaine (s50-r50) And Bupivacaine Enantiomeric Mixture (s75-r25): Cyclodextrins Complexation Effects On Sciatic Nerve Blockade In Mice [sistemas De Liberação Controlada Com Bupivacaína Racêmica (s50-r50) E Mistura Enantiomérica De Bupivacaína (s75-r25): Efeitos Da Complexaćão Com Ciclodextrinas No Bloqueio Do Nervo Ciático Em Camundongos]

BACKGROUND AND OBJECTIVES: Bupivacaine-induced side effects have led to the search for new local anesthetics (LA) with similar potency and lower toxicity, such as bupivacaine enantiomeric mixture (S75-R25). Drug-delivery systems for LA in carriers, such as cyclodextrins (CD), have been developed to improve anesthetic potency and therapeutic index of those drugs. This study aimed at preparing, characterizing and evaluating the anesthetic efficacy of inclusion complexes of bupivacaine enantiomeric mixture (S75-R25) and racemic bupivacaine (S50-R50) with hydroxypropylβ- cyclodextrin (HPβ-CD) comparing them to clinically available preparations. METHODS: Inclusion complexes were obtained by mixing appropriate volumes of HPβ-CD and S50-R50 or S75-R25 to final 1:1 or 1:2 molar ratios and were characterized by phase solubility experiments. Affinity constants (K) were determined between HPβ-CO and each LA. Motor and sensory blocks induced by plain or complexed LA formulations were evaluated in mice by sciatic nerve block. Three LA concentrations were used during the experiment: 0.125, 0.25 and 0.5%. RESULTS: Solubility experiments results were indicative of S50-R50:HPβ-CD and S75-R25:HPβ-CD complexation, with similar affinity constant (K) values: 14.7 M -1 and 14.3 M -1, respectively. In vivo experiments have shown that complexation has enhanced differential nerve blockade induced by LA: i) motor blockade duration induced by S75-R25 was similar, to the induced by but less intense S50-R50 (p < 0.001). S50-R50 HPβ-CD and S75-R25 HPβ-CD complexes have decreased onset (p < 0.01 and p < 0.05. respectively), without changing motor block intensity (E max) as compared to plain drugs; ii) sensory block evaluation has revealed higher analgesic intensity with S50-R50 HPβ-CD (2-fold, p < 0.001) and S75-R25 HPβ-CD (1.5-1.8-fold, p < 0.01 and p < 0.001, respectively) with both molar ratios (1:1 and 1:2, LA:CD), in addition to prolonging analgesic effect as compared to S50-R50 and S75-R25. CONCLUSIONS: More pronounced analgesic effects obtained by complexation with HPβ-CD have shown that both formulations. S50-R50 HPβ-CD, are S75-R25 HPβ-CD, are very useful for postoperative pain relief, requiring lower LA concentrations. Nevertheless, it is worth noticing that S75-R25 - being less toxic than racemic bupivacaine - is an interesting alternative for the development of more effective and safe drug-delivery systems as compared to racemic bupivacaine (S50-R50). © Sociedade Brasileira de Anestesiologia, 2005.553316328Mather, L.E., Chang, D.H., Cardiotoxicity with modern local anesthetics: Is there a safer choice? (2001) Drugs, 61, pp. 333-342Ohmura, S., Kawada, M., Ohta, T., Systemic toxicity and resuscitation in bupivacaine, levobupivacaine, or ropivacaine-infused rats (2001) Anesth Analg, 93, pp. 743-748Santos, A.C., Dearmas, P.I., Systemic toxicity of levobupivacaine, bupivacaine and ropivacaine during continuous intravenous infusion to nonpregnant and pregnant ewes (2001) Anesthesiology, 95, pp. 1256-1264Whiteside, J.B., Wildsmith, J.A., Developments in local anesthesia drugs (2001) Br J Anaesth, 87, pp. 27-35Simonetti, M.P.B., Batista, R.A., Ferreira, F.M.C., Estereoisomeria: A interface da tecnologia industrial de medicamentos e da racionalização terapêutica (1998) Rev Bras Anestesiol, 48, pp. 390-399Araujo, D.R., Pinto, L.M.A., Braga, A.F.A., Formulações de anestésicos locais de liberação controlada: Aplicações terapêuticas (2003) Rev Bras Anestesiol, 53, pp. 663-671Szejtli, J., Medicinal applications of cyclodextrins (1994) Med Res Rev, 14, pp. 353-386Freville, J.C., Dollo, G., Le Corre, P., Controlled systemic absorption and increased anesthetic effect of bupivacaine following epidural administration of bupivacaine-hydroxypropyl-beta- cyclodextrin complex (1996) Pharm Res, 13, pp. 1576-1580Dollo, G., Thompson, D.O., Le Corre, P., Inclusion complexation of amide-type local anesthetics with β-cyclodextrin and derivates. III. Biopharmaceutics of bupivacaine-SBE7- β-CD complex following percutaneous sciatic nerve administration in rabbits (1998) Int J Pharm, 164, pp. 11-19Dollo, G., Le Corre, P., Freville, J.C., Biopharmaceutics of local anesthetic-cyclodextrin complexes following loco-regional administration (2000) Ann Pharm Fr, 58, pp. 425-432Estebe, J.P., Ecoffey, C., Dollo, G., Bupivacaine pharmacokinetics and motor blockade following epidural administration of the bupivacaine- sulphobutylether -7-beta-cyclodextrin complex in sheep (2002) Eur J Anaesthesiol, 19, pp. 308-310Higuchi, T., Connors, K.A., Phase-solubility techniques (1965) Adv Anal Chem Instr, 4, pp. 117-212De Paula, E., Schreier, S., Use of a novel method for determination of partition coefficients to compare the effect of local anesthetics on membrane structure (1995) Biochim Biophys Acta, 1240, pp. 25-33Leszczynska, K., Kau, S.T., A sciatic nerve blockade method to differentiate drug-induced local anesthesia from neuromuscular blockade in mice (1992) J Pharmacol Toxicol Methods, 27, pp. 85-93Gantenbein, M., Abat, C., Attolini, L., Ketamine effects on bupivacaine local anaesthetic activity and pharmacokinetics of bupivacaine in mice (1997) Life Sci, 61, pp. 2027-2033Randall, L.O., Selitto, J.J., A method for measurement of analgesic activity of inflamed tissue (1957) Arch Int Pharmacodyn, 11, pp. 409-419De Araujo, D.R., Cereda, C.M., Brunetto, G.B., Encapsulation of mepivacaine prolongs the analgesia provided by sciatic nerve blockade in mice (2004) Can J Anaesth, 51, pp. 566-572Zar, J.H., (1996) Biostatistical Analysis, 3 rd Ed., pp. 180-216. , New Jersey, Prentice-HallDollo, G., Le Corre, P., Chevanne, F., Inclusion complexation of amide-type local anesthetics with β-cyclodextrin and derivates. II. Evaluation of affinity constants and in vitro transfer rate constants (1996) Int J Pharm, 136, pp. 165-174Simonetti, M.P.B., Valinetti, E.A., Ferreira, F.M., Avaliação da atividade anestésica local da S(-) bupivacaína: Estudo experimental in vivo em nervo ciático de rato (1997) Rev Bras Anestesiol, 47, pp. 425-434Sinnott, C.J., Strichartz, G.R., Levobupivacaine versus ropivacaine for sciatic nerve block in the rat (2003) Reg Anesth Pain Med, 28, pp. 294-303Tanaka, P.P., Souza, R.O., Salvalaggio, M.F.O., Estudo comparativo entre a bupivacaína a 0.5% e a mistura enantiomérica de bupivacaína (S75-R25) a 0.5% em anestesia peridural em pacientes submetidos a cirurgia ortopédica de membros inferiores (2003) Rev Bras Anestesiol, 53, pp. 331-337Cortes, C.A.F., Oliveira, A.S., Castro, L.F.L., Estudo comparative entre bupivacaína a 0.5%, mistura enantiomérica de bupivacaína (S75-R25) a 0.5% e ropivacaína a 0.75% associadas ao fentanil em anestesia peridural para cesarianas (2003) Rev Bras Anestesiol, 53, pp. 177-187Gonçalves, R.F., Lauretti, G.R., Mattos, A.L., Estudo comparative entre bupivacaína a 0.5% e mistura enantiomérica de bupivacaína (S75-R25) a 0.5% em anestesia peridural (2003) Rev Bras Anestesiol, 53, pp. 169-17

Preparação e caracterização inicial de complexo de inclusão entre nitrofurazona e 2-hidroxipropil-β-ciclodextrina

Nitrofurazone (NF), 5-nitro-2-furaldehyde semicarbazone, a broad-spectrum antibiotic, has reported toxic effects and low solubility in water. It would be of great interest to form inclusion complexes between NF and a cyclodextrin, to develop more effective and safer antibiotic formulations. This paper focuses on the preparation of inclusion complexes of NF with 2-hydroxypropyl-β- cyclodextrin (HP-β-CD) and their initial characterization by evaluating rates of complex formation, photostability, solubility isotherms, release rate profiles, stoichiometry of the complexes and their morphology, as revealed by scanning electron microscopy. The kinetic tests of complex formation revealed that 17,3 h is enough for stabilization of the NF-cyclodextrin complex. The solubility isotherm studies showed that the isotherm changes from type A to type B, as a function of temperature. The photostability experiments showed that the insertion of the NF in the HP-β-CD cavity protects the drug from photodecomposition. The release kinetic tests showed that the profile of NF release from the complex is altered by the presence of HP-β-CD in the medium. A Job's plot indicated that the stoichiometry of the complex was 1:1 NF:HP-β-CD. The scanning electron micrographs showed changes in the crystal structure of NF in the complex. This study focused on the physicochemical properties of drug-delivery formulations that could potentially be developed into a novel type of therapy with NF.Nitrofurazona (NF), 5-nitro-2-furaldeído semicarbazona, é um antibiótico de amplo espectro, que apresenta diversos efeitos tóxicos e baixa solubilidade aquosa. A complexação da NF com ciclodextrinas é de grande interesse para o desenvolvimento de uma formulação para este antibiótico que seja mais segura e eficiente. Neste trabalho foi realizada a preparação e caracterização inicial do complexo de inclusão entre NF e hidroxipropil-ß-ciclodextrina (HP-ß-CD) através de experimentos para determinação da cinética de complexação, medidas de fotoestabilidade, medidas de constante de afinidade fármaco: ciclodextrina, ensaios de liberação in vitro, estequiometria de formação do complexo e morfologia do complexo por microscopia eletrônica de varredura. Os ensaios de cinética de complexação mostram que para o complexo atingir o equilíbrio são necessárias 17,3h. As isotermas de solubilidade determinadas para a NF em função da temperatura mostraram perfis do tipo A e B indicando que a temperatura é um fator importante na complexação da NF com ciclodextrina. Os experimentos de fotoestabilidade indicam que a inserção da molécula de NF na cavidade interna da ciclodextrina protege o fármaco da fotodecomposição. A cinética de liberação mostra que o perfil de liberação do fármaco é modificado pela presença da ciclodextrina no meio. A estequiometria de complexação entre NF e HP-ß-CD determinada foi de 1:1 NF:HP-ß-CD. Os resultados de microscopia eletrônica de varredura indicam alterações na estrutura cristalina da NF em presença de ciclodextrina. Este estudo está baseado na caracterização físico-química da complexação entre NF e HP-ß-CD podendo ser uma nova potencial opção para utilização terapêutica do NF. Palavras-chave: nitrofurazona; ciclodextrina; complexo de inclusão

Controlled release system for ametryn using polymer microspheres: Preparation, characterization and release kinetics in water

The purpose of this work was to develop a modified release system for the herbicide ametryn by encapsulating the active substance in biodegradable polymer microparticles produced using the polymers poly(hydroxybutyrate) (PHB) or poly(hydroxybutyrate-valerate) (PHBV), in order to both improve the herbicidal action and reduce environmental toxicity. PHB or PHBV microparticles containing ametryn were prepared and the efficiencies of herbicide association and loading were evaluated, presenting similar values of approximately 40%. The microparticles were characterized by scanning electron microscopy (SEM), which showed that the average sizes of the PHB and PHBV microparticles were 5.92 +/- 0.74 mu m and 5.63 +/- 0.68 mu m, respectively. The ametryn release profile was modified when it was encapsulated in the microparticles, with slower and more sustained release compared to the release profile of pure ametryn. When ametryn was associated with the PHB and PHBV microparticles, the amount of herbicide released in the same period of time was significantly reduced, declining to 75% and 87%, respectively. For both types of microparticle (PHB and PHBV) the release of ametryn was by diffusion processes due to anomalous transport (governed by diffusion and relaxation of the polymer chains), which did not follow Fick's laws of diffusion. The results presented in this paper are promising, in view of the successful encapsulation of ametryn in PHB or PHBV polymer microparticles, and indications that this system may help reduce the impacts caused by the herbicide, making it an environmentally safer alternative. (C) 2010 Elsevier B.V. All rights reserved

Zein Nanoparticles as Eco-Friendly Carrier Systems for Botanical Repellents Aiming Sustainable Agriculture

Botanical repellents represent one of the main ways of reducing the use of synthetic pesticides and the contamination of soil and hydric resources. However, the poor stability and rapid degradation of these compounds in the environment hinder their effective application in the field. Zein nanoparticles can be used as eco-friendly carrier systems to protect these substances against premature degradation, provide desirable release characteristics, and reduce toxicity in the environment and to humans. In this study, we describe the preparation and characterization of zein nanoparticles loaded with the main constituents of the essential oil of citronella (geraniol and <i>R</i>-citronellal). The phytotoxicity, cytotoxicity, and insect activity of the nanoparticles toward target and nontarget organisms were also evaluated. The botanical formulations showed high encapsulation efficiency (>90%) in the nanoparticles, good physicochemical stability, and effective protection of the repellents against UV degradation. Cytotoxicity and phytotoxicity assays showed that encapsulation of the botanical repellents decreased their toxicity. Repellent activity tests showed that nanoparticles containing the botanical repellents were highly repellent against the <i>Tetranychus urticae</i> Koch mite. This nanotechnological formulation offers a new option for the effective use of botanical repellents in agriculture, reducing toxicity, protecting against premature degradation, and providing effective pest control