[Show abstract][Hide abstract] ABSTRACT: Abstract Objective: To characterize liposomal-lidocaine formulations for topical use on oral mucosa and to compare their in vitro permeation and in vivo anesthetic efficacy with commercially available lidocaine formulations. Materials and methods: Large unilamellar liposomes (400 nm) containing lidocaine were prepared using phosphatidylcholine, cholesterol, and α-tocoferol (4:3:0.07, w:w:w) and were characterized in terms of membrane/water partition coefficient, encapsulation efficiency, size, polydispersity, zeta potential, and in vitro release. In vitro permeation across pig palatal mucosa and in vivo topical anesthetic efficacy on the palatal mucosa in healthy volunteers (double-blinded cross-over, placebo controlled study) were performed. The following formulations were tested: liposome-encapsulated 5% lidocaine (Liposome-Lido5); liposome-encapsulated 2.5% lidocaine (Liposome-Lido2.5); 5% lidocaine ointment (Xylocaina®), and eutectic mixture of lidocaine and prilocaine 2.5% (EMLA®). Results: The Liposome-Lido5 and EMLA showed the best in vitro permeation parameters (flux and permeability coefficient) in comparison with Xylocaina and placebo groups, as well as the best in vivo topical anesthetic efficacy. Conclusion: We successfully developed and characterized a liposome encapsulated 5% lidocaine gel. It could be considered an option to other topical anesthetic agents for oral mucosa.
Journal of Liposome Research 05/2014; · 1.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Poloxamers (PL) are copolymers A-B-A type consisting of ethylene oxide (EO) and propylene oxide (PO) units in a triblock EOx–POy–EOx arrangement. These copolymers are interesting due to their ability for temperature-dependent gel formation, as a result of their self-assembling in micelles. Several studies have demonstrated the application of the thermoreversible copolymers as drug-delivery systems in order to prolong the drug release, to sustain the effectiveness, and also to reduce local and/or systemic toxicity, connecting the expertise of different research fields such as Biochemistry, Nanotechnology, Biopharmaceutics, Pharmacology, and Toxicology. Then, the purpose of this chapter involves a discussion about PL copolymers in the light of those research fields. The development of one-type or binary PL carriers systems is a function of composition (type of copolymer, differences on EO/PO units number, molecular weight), physicochemical properties (hydrophilic-lipophilic balance, cloud point, critical micellar concentration), and structural parameters such as micellar size, temperature for micelles, and hydrogels assembling. Besides, for focusing on how PL can be useful to achieve sustained drug release it is necessary to consider their pharmacological properties (such as the ability to inhibit the P-glycoprotein), in vitro (cytotoxicity or cytoprotection and their mechanisms) and in vivo toxicological evaluation (biocompatibility and regulatory aspects).
[Show abstract][Hide abstract] ABSTRACT: Introduction: Dermal and transdermal drug delivery systems offer the possibility to control the release of the drug for an extended period of time. In particular, skin-delivery of local anesthetics (LA) is one of the most important strategies to increase the local drug concentration and to reduce systemic adverse reactions. Areas covered: During the development phase of new formulations for skin-delivery of LA one should consider a set of desirable features such providing suitable adhesion, easy application/removal and also to be biocompatible, biodegradable and non-toxic. This review emphasizes the main strategies for skin-delivery of LA considering those features in relation to the composition of the delivery systems described. The topics highlight the relationships between physico-chemical studies and pharmaceutical applications for liposomes and solid lipid nanoparticles as well as the formulation and clinical applications for hydrogels and patches. Expert opinion: The development of LA skin-delivery systems using hydrogels and different permeation enhancers, liposomes or lipid nanoparticles (as isolated carrier systems or as their dispersion in a gel-base) and patches have been explored as alternatives to commercial formulations, modifying the release rate of LA, increasing bioadhesive properties and reducing toxicity, resulting in an improved therapeutic efficacy. This review should provide to the reader a special emphasis on four delivery-systems, comprising the group of liposomes and lipid nanoparticles, hydrogels and patches technologies looking forward their application for skin anesthesia.
Expert Opinion on Drug Delivery 08/2013; · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Microtubes obtained from the self-assembly of L-diphenylalanine (FF-MTs) were evaluated as potential vehicles for intracellular delivery. The biological marker Rhodamine B (RhB) was chosen as a model drug and conjugated to the peptide arrays during self-organization in the liquid phase. Microscopy and X-ray studies were performed to provide morphological and structural information. The data revealed that the cargo was distributed either in small aggregates at the hydrophobic surface of the FF-MTs or homogeneously embedded in the structure, presumably anchored at polar sites in the matrix. Raman spectroscopy revealed notable shifts of the characteristic RhB resonance peaks, demonstrating the successful conjugation of the fluorophore and peptide assemblies. In vitro assays were conducted in erythrocytes and fibroblast cells. Interestingly, FF-MTs were found to modulate the release of the load. The release of RhB from the FF-MTs followed first-order kinetics with a steady-state profile, demonstrating the potential of these carriers to deliver drugs at constant rates in the body. Cytotoxicity investigations revealed high cell viability up to concentrations of 5 mg mL-1, demonstrating the low toxicity of the FF-MTs.
[Show abstract][Hide abstract] ABSTRACT: Abstract Gel formulations containing the local anesthetic butamben (BTB) encapsulated in either conventional (BTBLUV) or elastic (BTBLUV-EL) liposomes were prepared and characterized, and then evaluated in terms of their skin permeability. Parameters measured included vesicle size and surface charge, BTB fluorescence anisotropy, encapsulation efficiency, partition coefficient and liposomal membrane organization. Encapsulation efficiencies and membrane/water partition coefficients were determined using a phase separation. The partition coefficients of the elastic and conventional formulations were 2025 ± 234 and 1136 ± 241, respectively. The sizes of the elastic and conventional liposomes did not change significantly (p > 0.05) following incorporation of the anesthetic. As expected, the elastic liposomes presented order parameters that were lower than those of the conventional liposomes, as determined by electron paramagnetic resonance with a 5-stearic acid nitroxide probe incorporated into the bilayer. After 8 h, the fluxes into the receiving solution (µg/cm(2)/h) were 6.95 ± 1.60 (10% BTB), 23.17 ± 6.09 (10% BTBLUV) and 29.93 ± 6.54 (10% BTBLUV-EL). The corresponding time lags (h) were 1.90 ± 0.48, 1.23 ± 0.28 and 1.57 ± 0.38, respectively. The permeability coefficients (10(-3 )cm/h) were 1.02 ± 0.23, 2.96 ± 0.77 and 4.14 ± 0.9, for 10% BTB, 10% BTBLUV and 10% BTBLUV-EL, respectively. The results demonstrate that anesthetic access through the skin can be considerably enhanced using liposomal gel formulations, compared to plain gel formulations.
Journal of Liposome Research 05/2013; · 1.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dibucaine (DBC) is powerful long-lasting local anesthetic, but it is
also considered fairly toxic to the CNS. Solid lipid nanoparticles (SLN)
and nanostructured lipid carriers (NLC) have attracted attention as
carriers for drug delivery. The aim of this study was to develop and to
evaluate the cytotoxic activity of DBC-loaded SLN and NLC against 3T3
fibroblast and HaCat keratinocyte cells. The SLN and NLC had myristyl
myristate and Liponate®GC as their lipid matrices, respectively,
plus a surfactant. SLN and NLC were characterized in terms in their
diameter, size distribution, surface charge and DBC encapsulation
efficiency. The particle size of SLN and NLC were around 234.33 and
166.62 nm, respectively. The polydispersity index was kept below 0.2 for
both nanomaterials. Negative surface charges were observed for both
nanoparticles, which decreased in the presence of the anesthetic.
Encapsulation efficiency reached 76% and 90%, respectively, in SLN and
NLC. DBC alone was found to be toxic to 3T3 and HaCat cells in culture.
However, NLC and SLN loaded DBC decreased its intrinsic cytotoxic effect
against 3T3 and HaCat cells. In conclusion, encapsulation of DBC in SLN
and NLC decreased the in vitro toxicity of the local anesthetic,
indicating the potential of these nanocarriers for clinical
Journal of Physics Conference Series 04/2013; 429(1):2035-.
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to characterize a liposome-based benzocaine (BZC) formulation designed for topical use on the oral mucosa and to evaluate its in vitro retention and permeation using the Franz-type diffusion cells through pig esophagus mucosa. To predict the effectiveness of new designed formulations during preclinical studies, a correlation between in vitro assays and in vivo efficacy was performed. Liposomal BZC was characterized in terms of membrane/water partition coefficient, encapsulation efficiency, size, polydispersity, zeta potential, and morphology. Liposomal BZC (BL10) was incorporated into gel formulation and its performances were compared to plain BZC gel (B10) and the commercially available BZC gel (B20). BL10 and B10 presented higher flux and retention on pig esophagus mucosa with a shorter lag time, when compared to B20. BZC flux was strongly correlated with in vivo anesthetic efficacy, but not with topical anesthesia duration. The retention studies did not correlate with any of the in vivo efficacy parameters. Thus, in vitro permeation study can be useful to predict anesthetic efficacy during preclinical tests, because a correlation between flux and anesthetic efficacy was observed. Therefore, in vitro assays, followed by in vivo efficacy, are necessary to confirm anesthetic performance.
Journal of Liposome Research 12/2012; · 1.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Expert Opinion on Drug Delivery 11/2012; · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bupivacaine (BVC) and ropivacaine (RVC) are local anesthetics widely used in surgical procedures. In previous studies, inclusion complexes of BVC or RVC in hydroxypropyl-β-cyclodextrin (HP-β-CD) increased differential nervous blockade, compared to the plain anesthetic solutions. In this study we evaluated the local neural and muscular toxicity of these new formulations containing 0.5% BVC or RVC complexed with HP-β-CD (BVC(HP-β-CD) and RVC(HP-β-CD)).
Schwann cell viability was assessed by determination of mitochondrial dehydrogenase activity, and histopathological evaluation of the rat sciatic nerve was used to identify local neurotoxic effects (48 hours and 7 days after the treatments). Evaluations of serum creatine kinase levels and the histopathology of rat gastrocnemius muscle (48 hours after treatment) were also performed.
Schwann cell toxicity evaluations revealed no significant differences between complexed and plain local anesthetic formulations. However, use of the complexed local anesthetics reduced serum creatine kinase levels 5.5-fold, relative to the plain formulations. The differences were significant at P < 0.05 (BVC) and P < 0.01 (RVC). The histopathological muscle evaluation showed that differences between groups treated with local anesthetics (BVC or RVC) and their respective complexed formulations (BVC(HP-β-CD) or RVC(HP-β-CD)) were significant (P < 0.05).
We concluded that the new formulations presented a lower myotoxicity and a similar cytotoxic effect when compared to plain local anesthetic solutions.
Anesthesia and analgesia 07/2012; 115(5):1234-41. · 3.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sufentanil (SUF) is a synthetic analgesic opioid widely used for the management of acute and chronic pain. This drug was complexed with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and the physicochemical characterization, in vitro/ex vivo toxicity assays, and pharmacological evaluation were performed. Differential scanning calorimetry, Fourier transform infrared spectroscopy (FTIR) analysis, and X-ray powder diffraction showed the formation and the morphology of the complex. Nuclear magnetic resonance afforded data regarding inclusion complex stoichiometry (1:1) with an association binding constant (K(a)) value of 515.2 ± 1.2 M(-1) between SUF and HP-β-CD. Complexation with HP-β-CD protected SUF from light exposure and increased its photostability. Release kinetics revealed a decrease in SUF release rate (K(rel) = 7.05 ± 0.52 and 5.61 ± 0.39 min(-1/2) for SUF-HP-β-CD and SUF, respectively) and reduced hemolytic or myotoxic effects after complexation. Time course of tail-flick test showed that the duration of analgesia induced by SUF (150.0 ± 34.6 min) was significantly increased (p < 0.001) after complexation with HP-β-CD (355.7 ± 47.2 min) when injected at the same dose (1 μg kg(-1)), prolonging the duration of analgesia after intramuscular administration and representing an alternative on the development of effective and safe drug-delivery system for opioid analgesics.
Journal of Pharmaceutical Sciences 06/2012; 101(10):3698-707. · 3.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pharmacokinetics of commercial and liposome-encapsulated mepivacaine (MVC) injected intra-orally in healthy volunteers was studied.
In this double blind, randomized cross-over study, 15 volunteers received, at four different sessions, 1.8 ml of the following formulations: 2% MVC with 1 : 100 000 epinephrine (MVC(2%EPI) ), 3% MVC (MVC(3%) ), 2% and 3% liposome-encapsulated MVC (MVC(2%LUV) and MVC(3%LUV) ). Blood samples were collected pre dose (0 min) and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 min after injections. Liquid chromatography-tandem mass spectrometry was used to quantify plasma MVC concentrations.
Pharmacokinetic analysis showed that the maximum plasma concentration (Cmax) and the areas under the curves (AUC(0-360) and AUC(0-∞)) after MVC(2%LUV) and MVC(2%EPI) injections were smaller (P < 0.05) than the equivalent figures for MVC(3%) and MVC(3%LUV). The time to maximum plasma concentration (Tmax) and the half-life of elimination (t½beta) obtained after the treatment with MVC(2%LUV), MVC(2%EPI), MVC(3%) and MVC(3%LUV) presented no statistically significant differences (P > 0.05). Cmax, AUC(0-360) and AUC(0-∞) after injection of the 2% formulations (MVC(2%LUV) and MVC(2%EPI) ) did not exhibit statistically significant differences (P > 0.05). The pharmacokinetics of MVC(2%LUV) were comparable to the pharmacokinetics of MVC(2%EPI).
The liposomal formulation of 2% MVC exhibits similar systemic absorption to the local anesthetic with vasoconstrictor.
The Journal of pharmacy and pharmacology. 03/2012; 64(3):397-403.
[Show abstract][Hide abstract] ABSTRACT: This paper describes a comparison of different polymeric nanocapsules (NCs) prepared with the polymers poly(D,L-lactide-co-glycolide), poly(L-lactide) (PLA), and poly(ε-caprolactone) and used as carrier systems for the local anesthetic (LA) benzocaine (BZC). The systems were characterized and their anesthetic activities investigated. The results showed particle size distributions with polydispersity indices below 0.135, average diameters up to 120 nm, zeta potentials up to -30 mV, and entrapment efficiencies around 70%. Formulations of BZC using the polymeric NCs presented slower release profiles, compared with that of free BZC. Slowest release (release constant, k = 0.0016 min(-1)) was obtained using the PLA NC system. Pharmacological evaluation showed that encapsulation of BZC in PLA NCs prolonged its anesthetic action. This new formulation could potentially be used in future applications involving the gradual release of local anesthetics (LAs).
Journal of Pharmaceutical Sciences 11/2011; 101(3):1157-65. · 3.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this work was to investigate the influence of the oily nucleus composition on physico-chemical properties and anesthetic activity of poly (lactide-co-glycolide) nanocapsules with benzocaine.
Nanocapsules containing benzocaine were prepared with three different oily nucleus composition and characterized by mean diameter, polydispersivity, zeta potential, pH and stability were investigated as a function of time. In vitro release kinetics were performed in a system with two compartments separated by a cellulose membrane. Intensity and duration of analgesia were evaluated in rats by sciatic nerve blockade.
The greatest stability, slower release profile and improvement in the local anesthetic activity of BZC were obtained with the formulation using USP mineral oil as component.
Results from our study provide useful perspectives on selection of the primary materials needed to produce suspensions of polymeric nanocapsules able to act as carriers of BZC, with potential future application in the treatment of pain.
Pharmaceutical Research 04/2011; 28(8):1984-94. · 4.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This blinded crossover study evaluated the efficacy and pain sensitivity evoked by a previously reported liposome-encapsulated mepivacaine formulation (Araujo et al., 2004). Thirty healthy volunteers received an intraoral injection (1.8 mL), at four different sessions, of the following formulations: 2% mepivacaine with 1:100,000 epinephrine (MVC(2%EPI)), 3% mepivacaine (MVC(3%)), and 2 and 3% liposome-encapsulated mepivacaine (MVC(2%LUV) and MVC(3%LUV)). Latency period and duration of anesthesia were assessed by an electrical pulp tester and injection discomfort by a visual analog scale (VAS). Data were analyzed with Tukey-Kramer and Friedman tests (P < 0.05). No significant difference was found regarding latency period (in minutes) among the formulations (P > 0.05). The duration of anesthesia after the injection of MVC(3%LUV) was higher than the one obtained after the infiltration of MVC(2%LUV) and of MVC(3%) (P < 0.05). However, the duration of anesthesia obtained with MVC(3%) did not differ from the one obtained with MVC(2%LUV) (P > 0.05). MVC(3%LUV) showed lower VAS median values than MVC(2%EPI) (P < 0.05), and there were no significant differences among the others formulations. Liposome-encapsulated 3% mepivacaine showed longer duration of anesthesia, in comparison to the commercial formulation of MVC(3%). MVC(2%LUV) was able to produce a similar duration of anesthesia as the 3% commercial formulation, despite the 50% decrease in the anesthetic concentration. Thus, the encapsulation of mepivacaine increased the duration of anesthesia and reduced the injection discomfort caused by vasoconstrictor-associated formulations in healthy volunteers.
Journal of Liposome Research 03/2011; 21(1):88-94. · 1.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cancer cells are the product of genetic disorders that alter crucial intracellular signaling pathways associated with the regulation of cell survival, proliferation, differentiation and death mechanisms. The role of oncogene activation and tumor suppressor inhibition in the onset of cancer is well established. Traditional antitumor therapies target specific molecules, the action/expression of which is altered in cancer cells. However, since the physiology of normal cells involves the same signaling pathways that are disturbed in cancer cells, targeted therapies have to deal with side effects and multidrug resistance, the main causes of therapy failure. Since the pioneering work of Otto Warburg, over 80 years ago, the subversion of normal metabolism displayed by cancer cells has been highlighted by many studies. Recently, the study of tumor metabolism has received much attention because metabolic transformation is a crucial cancer hallmark and a direct consequence of disturbances in the activities of oncogenes and tumor suppressors. In this review we discuss tumor metabolism from the molecular perspective of oncogenes, tumor suppressors and protein signaling pathways relevant to metabolic transformation and tumorigenesis. We also identify the principal unanswered questions surrounding this issue and the attempts to relate these to their potential for future cancer treatment. As will be made clear, tumor metabolism is still only partly understood and the metabolic aspects of transformation constitute a major challenge for science. Nevertheless, cancer metabolism can be exploited to devise novel avenues for the rational treatment of this disease.
Cellular Physiology and Biochemistry 01/2011; 28(5):771-92. · 3.42 Impact Factor