Eneida de Paula

Surface active drugs: self-association and interaction with membranes and surfactants. Physicochemical and biological aspects.

Many pharmacologically active compounds are of amphiphilic (or hydrophobic) nature. As a result, they tend to self-associate and to interact with biological membranes. This review focuses on the self-aggregation properties of drugs, as well as on their interaction with membranes. It is seen that drug-membrane interactions are analogous to the interactions between membranes and classical detergents. Phenomena such as shape changes, vesiculation, membrane disruption, and solubilization have been observed. At the molecular level, these events seem to be modulated by lipid flip-flop and formation of non-bilayer phases. The modulation of physicochemical properties of drugs by self-association and membrane binding is discussed. Pathological consequences of drug-membrane interaction are described. The mechanisms of drug solubilization by surfactants are reviewed from the physicochemical point of view and in relation to drug carrying and absorption by the organism.

Encapsulation of mepivacaine prolongs the analgesia provided by sciatic nerve blockade in mice.

PurposeLiposomal formulations of local anesthetics (LA) are able to control drug-delivery in biological systems, prolonging their anesthetic effect. This study aimed to prepare, characterize and evaluatein vivo drug-delivery systems, composed of large unilamellar liposomes (LUV), for bupivacaine (BVC) and mepivacaine (MVC).MethodsBVC and MVC hydrochloride were encapsulated into LUV (0.4 μm) composed of egg phosphatidylcholine, cholesterol and α-tocopherol (4:3:0.07 molar ratio) to final concentrations of 0.125, 0.25, 0.5% for BVC and 0.5, 1, 2% for MVC. Motor function and antinociceptive effects were evaluated by sciatic nerve blockade induced by liposomal and plain formulations in mice.ResultsLiposomal formulations modified neither the intensity nor the duration of motor blockade compared to plain solutions. Concerning sensory blockade, liposomal BVC (BVCLUV) showed no advantage relatively to the plain BVC injection while liposomal MVC (MVCLUV) improved both the intensity (1.4–1.6 times) and the duration of sensory blockade (1.3–1.7 times) in comparison to its plain solution (P < 0.001) suggesting an increased lipid solubility, availability and controlled-release of the drug at the site of injection.ConclusionMVCLUV provided a LA effect comparable to that of BVC. We propose MVCLUV drug delivery as a potentially new therapeutic option for the treatment of acute pain since the formulation enhances the duration of sensory blockade at lower concentrations than those of plain MVC.RésuméObjectifDes préparations liposomales d’anesthésiques locaux (AL) peuvent contrôler l’administration de médicaments dans les systèmes biologiques, prolongeant leur effet anesthésique. Notre objectif était de préparer, caractériser et évaluer des systèmes d’administration de médicaments in vivo, composés de gros liposomes unilamellaires (GLU), pour la bupivacaïne (BVC) et la mépivacaïne (MVC).MéthodeLe chlorhydrate de BVC et de MVC a été mis en capsules dans des GLU (0,4 μm) composés de lécithine d’œuf, de cholestérol et de α-tocophérol (concentration molaire 4:3:0,07) pour obtenir des concentrations finales de 0,125, 0,25, 0,5 % pour la BVC et 0,5, 1, 2 % pour la MVC. La fonction motrice et les effets antinociceptifs ont été évalués par le blocage du nerf sciatique induit par des préparations liposomales et des préparations simples chez des souris.RésultatsLes préparations liposomales, comparées aux préparations simples, n’ont pas modifié l’intensité ni la duré du bloc moteur. Quant au bloc sensitif, la BVC liposomale (BVCLUV) n’a pas présenté d’avantage par rapport à l’injection de BVC simple tandis que la MVC liposomale (MVCLUV) a amélioré l’intensité (1,4–1,6 fois) et la duré du bloc sensitif (1,3–1,7 fois) comparée à la solution simple (P < 0,001). Ce qui laisse croire à une meilleure solubilité lipidique, à une disponibilité accrue et à une meilleure administration du médicament à libération contrôlée au site de l’injection.ConclusionLa MVCLUV fournit un effet AL comparable à celui de la BVC. Nous proposons l’administration de MVCLUV comme un nouveau choix possible de traitement de la douleur aiguë, puisque la préparation augmente la durée du bloc sensitif à des concentrations plus faibles que celles de la MVC simple.

Liposomal formulations of prilocaine, lidocaine and mepivacaine prolong analgesic duration

PurposeA laboratory investigation was undertaken to compare the in vivo antinociceptive effects of 2% liposomal formulations of prilocaine (PLC), lidocaine (LDC) and mepivacaine (MVC) compared to plain solutions of each of these three local anesthetics.MethodsLarge unilamellar vesicles were prepared by extrusion (400 nm), at pH 7.4. The membrane/water partition coefficients were obtained from encapsulation efficiency values, after incorporation of each local anesthetic to the vesicles. The anesthetic effect of each liposomal formulation was compared to the respective local anesthetic solution in water, using the infraorbital nerve-blockade test, in rats.ResultsThe partition coefficients were: 57 for PLC, 114 for LDC and 93 for MVC. In vivo results showed that local anesthetic-free liposomes, used as control, had no analgesic effect. In contrast, the encapsulated formulations induced increased intensities of total anesthetic effect (35.3%, 26.1 % and 57.1 %) and time for recovery (percentage increases of 30%, 23.1 % and 56%), respectively, for PLC, LDC and MVC when compared to the plain solutions (P < 0.01).ConclusionsThese results indicate that liposomes provide effective drug-delivery systems for intermediate-duration local anesthetics. Mepivacaine was affected to the greatest extent, while LDC benefited least from liposome encapsulation, possibly due to greater vasodilatory properties of LDC.ObjectifUne recherche en laboratoire a été entreprise pour comparer les effets antinociceptifs in vivo de préparations liposomiques de prilocaïne (PLC), de lidocaïne (LDC) et de mépivacaïne (MVC) à 2 %, à des solutions simples de chacun de ces anesthésiques locaux.MéthodeDe grandes vésicules unilamellaires ont été préparées par extrusion (400 nm), à un pH de 7,4. Les coefficients de partage membrane/eau ont été obtenus des valeurs d’efficacité de l’encapsulation, après l’introduction de chaque anesthésique local dans les vésicules. L’effet anesthésique de chaque préparation liposomique a été comparé à la solution respective d’anesthésique local dans l’eau par le test de blocage du nerf infra-orbitaire chez des rats.RésultatsLes coefficients de partage ont été de : 57 pour la PLC, 114 pour la LDC et 93 pour la MVC. Les résultats in vivo ont montré que les liposomes témoins sans anesthésique local n’avaient pas d’effet analgésique. Par contre, les préparations en capsules ont augmenté l’intensité anesthésique totale (35,3 %, 26,1 % et 57,1 %) et le temps de récupération (30 %, 23,1 % et 56 %) respectivement pour la PLC, la LDC et la MVC comparées aux solutions simples (P < 0,01).ConclusionCes résultats indiquent que les liposomes sont des systèmes de vecteurs de médicaments efficaces pour les anesthésiques locaux de durée moyenne. La MVC a surtout bénéficié, et la LDC le moins, de l’encapsulation liposomique, peut-être à cause de ses plus importantes propriétés vasodilatatrices.

Drug Delivery Systems for Local Anesthetics

Although technological innovations in the area of drug delivery claim for varied benefits, increasing the drug therapeutic index for human clinical application is the main goal pursued. Drug delivery systems for local anesthetics (LA) have attracted researchers due to many biomedical advantages associated to their application. Formulation approaches to systemically deliver LA include the encapsulation in liposomes, complexation in cyclodextrins, association with biopolymers and others carrier systems. Topical delivery systems for LA are characteristically composed by a diversity of adjuvants (viscosity inducing agents, preservatives, permeation enhancers, emollients,) and presentations such as semisolid (gel, creams, ointments), liquid (o/w and w/o emulsions, dispersions) and solid (patches) pharmaceutical forms. The proposed formulations aims to reduce the LA concentration used, increase its permeability and absorption, keep the LA at the target site for longer periods prolonging the anesthetic or analgesic effect and, finally, to decrease the clearance, local and systemic toxicity. This review deals with the innovations pertaining to formulations and techniques for drug-delivery of topical and injectable local anesthetics, as described in recent patents.

Interaction of benzocaine with model membranes

We measured the absorption properties, water solubility and partition coefficients (P) between n-octanol, egg phosphatidylcholine (EPC) liposomes and erythrocyte ghosts/water for benzocaine (BZC), an ester-type always uncharged local anesthetic. The interaction of BZC with EPC liposomes was followed using Electron Paramagnetic Resonance, with spin labels at different positions in the acyl chain (5, 7, 12, 16-doxylstearic acid methyl ester). Changes in lipid organization upon BZC addition allowed the determination of P values, without phase separation. The effect of BZC in decreasing membrane organization (maximum of 11.6% at approx. 0.8:1 BZC:EPC) was compared to those caused by the local anesthetics tetracaine and lidocaine. Hemolytic tests revealed a biphasic (protective/inductive) concentration-dependent hemolytic effect for BZC upon rat erythrocytes, with an effective BZC:lipid molar ratio in the membrane for protection (RePROT), onset of hemolysis (ReSAT) and 100% membrane solubilization (ReSOL) of 1.0:1, 1.1:1 and 1.3:1, respectively. The results presented here reinforce the importance of considering hydrophobic interactions in the interpretation of the effects of anesthetics on membranes.

Polymeric alginate nanoparticles containing the local anesthetic bupivacaine

Bupivacaine (BVC; S75–R25, NovaBupi®) is an amide-type local anesthetic. Sodium alginate is a water-soluble linear polysaccharide. The present study reports the development of alginate/bis(2-ethylhexyl) sulfosuccinate (AOT) and alginate/chitosan nanoparticle formulations containing BVC (0.5%). The amounts of BVC associated in the alginate/AOT and alginate/chitosan nanoparticles were 87 ± 1.5 and 76 ± 0.9%, respectively. The average diameters and zeta potentials of the nanoparticles were measured for 30 days, and the results demonstrated the good stability of these particles in solution. The in vitro release kinetics showed a different behavior for the release profile of BVC in solution, compared with BVC-loaded alginate nanoparticles. In vitro and in vivo assays showed that alginate–chitosan BVC (BVCALG–CHIT) and alginate–AOT BVC (BVCALG–AOT) presented low cytotoxicity in 3T3-fibroblasts, enhanced the intensity, and prolonged the duration of motor and sensory blockades in a sciatic nerve blockade model.

Micro and nanosystems for delivering local anesthetics

Introduction: One of the most common strategies for pain control during and after surgical procedures is the use of local anesthetics. Prolonged analgesia can be safely achieved with drug delivery systems suitably chosen for each local anesthetic agent. Areas covered: This review considers drug delivery formulations of local anesthetics designed to prolong the anesthetic effect and decrease toxicity. The topics comprise the main drug delivery carrier systems (liposomes, biopolymers, and cyclodextrins) for infiltrative administration of local anesthetics. A chronological review of the literature is presented, including details of formulations as well as the advantages and pitfalls of each carrier system. The review also highlights pharmacokinetic data on such formulations, and gives an overview of the clinical studies published so far concerning pain control in medicine and dentistry. Expert opinion: The design of novel drug delivery systems for local anesthetics must focus on how to achieve higher uploads of the anesthetic into the carrier, and how to sustain its release. This comprehensive review should be useful to provide the reader with the current state-of-art regarding drug delivery formulations for local anesthetics and their possible clinical applications.

Pathways involved in trifluoperazine-, dibucaine- and praziquantel-induced hemolysis.

This work elucidates differences in the hemolytic pathway developed by the antipsychotic trifluoperazine (TFP), the local anesthetic dibucaine (DBC) and the antihelminthic praziquantel (PZQ). Their partition coefficients (P) were measured at pH 7.4 between n-octanol, microsomes, liposomes, erythrocyte ghosts and n-octanol/water. The effective drug:lipid molar ratios for the onset of membrane solubilization (ReSAT) and complete hemolysis (ReSOL) were calculated from the experimental P values and compared with a classical surface-active compound treatment Lichtenberg, D. Biochim. Biophys. Acta 821 (1985) 470-478[. The contribution of charged/uncharged forms of TFP and DBC for the hemolytic activity was also analyzed. In all cases the hemolytic phenomena could be related to the monomeric drug insertion into the membrane. Only for TFP at isosmotic condition lysis occurs at concentrations beyond the CMC of the drug, indicating that micellization facilitates TFP hemolytic effect, while DBC and PZQ reach a real membrane saturation at their monomeric form.

Contribution of trifluoperazine/lipid ratio and drug ionization to hemolysis

The interaction of the antipsychotic drug trifluoperazine (TFP) with membranes was investigated in terms of lipid phase perturbation. TFP partition coefficients (P) were measured by phase separation between octanol/water and model membranes/water. The profile of P values at pH 7.4 was: microsomes (7172+/-1229)>liposomes (1916+/-341)>erythrocyte ghosts (1380+/-429)>octanol (452+/-55). Hemolytic experiments showed a biphasic, protective (at lower concentrations) and hemolytic effect above the CMC (42 microM at pH 7.4) of the phenothiazine. By applying classical treatments for surface active compounds to the hemolytic curves, we could calculate P values in whole erythrocyte cells. The preferential binding of uncharged to charged TFP in the membrane was discussed, since it results in a ionization constant (pKapp) different from that observed in the aqueous phase (pK). The TFP ionization constant was decreased from 8.1 (in water) to 7.62 in the presence of membranes and almost the same ratio of charged/uncharged TFP species is present at physiologic pH. Taking into account the DeltapK, we calculated the average TFP partition coefficient between egg phosphatidylcholine liposomes and water, at pH 7.4 (Paverage=1432), which was well correlated with the measured one (Plip=1916). Paverage is highly influenced by the uncharged TFP species and the real base/acid ratio under physiologic conditions was discussed in terms of its possible role in the biological activity of TFP.

Liposome-encapsulated ropivacaine for topical anesthesia of human oral mucosa.

BACKGROUND:The elimination of pain caused by needle insertion for local anesthesia would be a significant advance in dentistry. METHODS:In this blinded cross-over study we evaluated the efficacy of liposome-encapsulated ropivacaine for topical anesthesia. Thirty healthy volunteers received 60 mg topical anesthetics: Liposome-encapsulated 1% ropivacaine, 1% plain ropivacaine, 2.5% lidocaine and 2.5% prilocaine mixture (EMLA), and 20% benzocaine gel, in the buccal fold of the upper-right canine for 2 min in different sessions. After insertion of 30-G needles, pain was rated on a visual analog scale (VAS). A pinprick test was used to measure the duration of topical anesthesia. The pulpar response was assessed by an electric pulp tester. RESULTS:VAS median and interquartile range (in cm) were 0.8 (0.4–1.5), 1.6 (0.8–2.6), 1.1 (0.3–2.7), 2.2 (0.9–2.9) for liposome-encapsulated ropivacaine, ropivacaine, EMLA, and benzocaine groups, respectively. The liposome-encapsulated ropivacaine group showed lower VAS mean values when compared with the benzocaine group (P = 0.0205). The median values and interquartile range for the duration of soft tissue anesthesia were 11 (7–14), 6.5 (4–11), 14 (11–16), and 7 (6–9) min for liposome-encapsulated ropivacaine, ropivacaine, EMLA, and benzocaine groups, respectively. EMLA and liposome-encapsulated ropivacaine were just as efficient for reducing pain, and showed longer soft tissue anesthesia when compared to the other local anesthetics (P = 0.0001). CONCLUSION:Liposomal-encapsulated 1% ropivacaine gel was equivalent to EMLA® for reducing pain during needle insertion and for the duration of soft tissue anesthesia. None of the topical anesthetics was effective for inducing pulpal anesthesia.