MARGARETH KAZUYO KOBAYASHI DIAS FRANCO

MARGARETH KAZUYO KOBAYASHI DIAS FRANCO

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Influence of structural organization on mucoadhesive properties of poloxamer-hyaluronic acid-based micelles and hydrogels
2024 - SEPULVEDA, ANDERSON F.; SILVA, JESSICA B. da; BRUSCHI, MARCOS L.; FRANCO, MARGARETH K.K.D.; YOKAICHIYA, FABIANO; TOFOLI, GIOVANA R.; CEREDA, CINTIA M.S.; ROSSO, ANABELLA P.; GIACOMELLI, FERNANDO C.; SCOTT, ANA L.; ARAUJO, DANIELE R. de
New pharmaceutical formulations have been proposed as strategies to improve transport and provide best conditions to control the drug release rate in specific biological environments, such as mucosa surfaces. Herein, formulations containing binary systems Poloxamer (PL) 407 15 % and PL 338 15 %, combined with hyaluronic acid, carrying the local anesthetic bupivacaine (BVC), were studied by molecular dynamics, while other structural parameters were determined by Dynamic Light Scattering for stablishing relationships with mucoadhesive properties and cytotoxicity evaluation. The binary system PL 407 15 %/PL 338 15 % exhibited a well-organized structural morphology, with more hydrated corona, and increased mucoadhesive properties over mucin layers. After hyaluronic acid (HA) incorporation, it was observed an increase on the force of detachment, possibly due to HA role as a linker among mucin layers independently of PL supramolecular structures. On the other hand, the addition of BVC or HA/BVC into the binary system decreased the force of detachment, as a response of augmented of compactness of these hydrogels caused by desolvation of PO core, showing the influence of all components and their chemical interactions into the structural organization and their biopharmaceutical performance relationships.
Fresh carrier for an old topical local anesthetic
2024 - SOUZA, A.D.; SILVA, G.H.R. da; RIBEIRO, L.N.M.; MITSUTAKE, H.; BORDALLO, H.N.; BREITKREITZ, M.C.; FERNANDES, P.C.L.; MOURA, L.D.; YOKAICHIYA, F.; FRANCO, M.; PAULA, E. de
Nanostructured lipid carriers (NLC) have emerged as innovative drug delivery systems, offering distinct advantages over other lipid-based carriers, such as liposomes and solid lipid nanoparticles. Benzocaine (BZC), the oldest topical local anesthetic in use, undergoes metabolism by pseudocholinesterase, leading to the formation of p-aminobenzoic acid, a causative agent for allergic reactions associated with prolonged BZC usage. In order to mitigate adverse effects and enhance bioavailability, BZC was encapsulated within NLC. Utilizing a 23 factorial design, formulations comprising cetyl palmitate (solid lipid), propylene glycol monocaprylate (liquid lipid), and Pluronic F68 as surfactants were systematically prepared, with variations in the solid/liquid lipid mass ratios (60:40-80:20%), total lipid contents (15-25%), and BZC concentrations (1-3%). The optimized formulation underwent characterization by dynamic light scattering, differential scanning calorimetry, Raman imaging, X-ray diffraction, small-angle neutron scattering, nanotracking analysis, and transmission electron microscopy (TEM)/cryo-TEM, providing insights into the nanoparticle structure and the incorporation of BZC into its lipid matrix. NLCBZC exhibited a noteworthy encapsulation efficiency (%EE = 96%) and a 1 year stability when stored at 25 °C. In vitro kinetic studies and in vivo antinociceptive tests conducted in mice revealed that NLCBZC effectively sustained drug release for over 20 h and prolonged the anesthetic effect of BZC for up to 18 h. We therefore propose the use of NLCBZC to diminish the effective anesthetic concentration of benzocaine (from 20 to 3% or less), thus minimizing allergic reactions that follow the topical administration of this anesthetic and, potentially, paving the way for new routes of BZC administration in pain management.
Structural characterization of silver nanoparticles produced by biogenic synthesis using SAXS
2024 - RIBEIRO JUNIOR, ARI; YOKAICHIYA, FABIANO; MONERJAN, ENELI; LEMKE, KARINA; GUILGER-CASAGRANDE, MARIANA; LIMA, RENATA; FRACETO, LEONARDO; FRANCO, MARGARETH K.K.D.; KELLERMANN, GUINTHER
Nanotechnology applied to the agricultural sector has highlighted in recent decades, making important contributions, including systems for pest control as biogenic nanoparticles. These nanoparticles are used to control phytopathogens, demonstrating the need to understand its composition, mechanisms of action and toxicity. Their capping of biomolecules, derived from the organism used in the synthesis, contributes to their stability and biological activity. Ag nanoparticles were produced by the fungus Trichoderma harzianum in aqueous solutions containing silver nitrate as a precursor for the silver nanoparticles. Some of the samples were exposed to the phytopathogenic fungus Sclerotinia sclerotiorum responsible for the white mold. After preparation, a fraction of the samples was submitted to physico-chemical processes to remove organic cap layer on nanoparticles surface formed during the preparation process. In this study we determined the effect of the phytopathogenic fungus and cap removal process in the average radius, radius dispersion, number density of the nanoparticles using small angle X-ray scattering (SAXS), where we considered their almost spherical shape in aqueous solution obtained by the biogenic route. The SAXS data analyses suggest that the presence of the pathogenic fungus results in a diminution of number and total volume of Ag NPs without significant effects on average radius and radius dispersion. Our results also indicate that the physic-chemical process to remove the organic cap surrounding the Ag NPs leads to a decrease in the fraction of the smaller nanoparticles.
A pre‑formulation study of tetracaine loaded in optimized nanostructured lipid carriers
2021 - CASTRO, SIMONE R.; RIBEIRO, LIGIA N.M.; BREITKREITZ, MARCIA C.; GUILHERME, VIVIANE A.; SILVA, GUSTAVO H.R. da; MITSUTAKE, HERY; ALCANTARA, ANA C.S.; YOKAICHIYA, FABIANO; FRANCO, MARGARETH K.K.D.; CLEMENS, DANIEL; KENT, BEN; LANCELLOTTI, MARCELO; ARAUJO, DANIELE R. de; PAULA, ENEIDA de
Tetracaine (TTC) is a local anesthetic broadly used for topical and spinal blockade, despite its systemic toxicity. Encapsulation in nanostructured lipid carriers (NLC) may prolong TTC delivery at the site of injection, reducing such toxicity. This work reports the development of NLC loading 4% TTC. Structural properties and encapsulation efficiency (%EE > 63%) guided the selection of three pre-formulations of different lipid composition, through a 23 factorial design of experiments (DOE). DLS and TEM analyses revealed average sizes (193–220 nm), polydispersity (< 0.2), zeta potential |− 21.8 to − 30.1 mV| and spherical shape of the nanoparticles, while FTIR-ATR, NTA, DSC, XRD and SANS provided details on their structure and physicochemical stability over time. Interestingly, one optimized pre-formulation (CP-TRANS/TTC) showed phase-separation after 4 months, as predicted by Raman imaging that detected lack of miscibility between its solid (cetyl palmitate) and liquid (Transcutol) lipids. SANS analyses identified lamellar arrangements inside such nanoparticles, the thickness of the lamellae been decreased by TTC. As a result of this combined approach (DOE and biophysical techniques) two optimized pre-formulations were rationally selected, both with great potential as drug delivery systems, extending the release of the anesthetic (> 48 h) and reducing TTC cytotoxicity against Balb/c 3T3 cells.
Complexation of the local anesthetic pramoxine with hydroxypropyl-beta-cyclodextrin can improve its bioavailability
2020 - BEZAMAT, JULIANA M.; YOKAICHIYA, FABIANO; FRANCO, MARGARETH K.K.D.; CASTRO, SIMONE R.; PAULA, ENEIDA de; CABEÇA, LUIS F.
Local anesthetics are widely used in clinical procedures, to eliminate pain during/after invasive procedures. A wide range of drug delivery systems has been developed to improve the effect of local anesthetics and/or to reduce their toxicity. Pramoxine (PMX) is a topical anesthetic agent with an unusual (morpholine ring) structure and low solubility (ca. 3 mM at pH 7.4). In this work, a novel formulation was devised for PMX in hydroxypropyl- β-cyclodextrin (HP-β-CD). Host-guest inclusion complex was prepared by the co-solubilization method, with complexation kinetics of 10 h, and 1:1 PMX/HP-β-CD stoichiometry. Complexation promoted 14-fold increase in the solubility of PMX. X-ray diffraction measurements revealed loss of the crystalline PMX pattern in the presence of HP-β-CD, an indication of inclusion complexation. Using 1H NMR (DOSY) experiments the association constant of PMX to HP-β-CD (Ka = 923.1 mol/L) was determined, while nuclear Overhauser (ROESY) analysis confirmed the formation of PMX/HP-β-CD inclusion complex, by detection of spatial proximities between hydrogens from PMX aromatic ring and cyclodextrin's cavity. In two in vitro toxicity models (mouse 3T3 fibroblasts in culture and red blood cells hemolysis) pramoxine toxicity was significantly reduced upon complexation into HP-β-CD. These results point out PMX/HP-β-CD as a promising pharmaceutical formulation to improve the bioavailability of pramoxine, allowing its application beyond topical anesthesia.
Poloxamer 407/188 binary thermosensitive hydrogels as delivery systems for infiltrative local anesthesia: Physico-chemical characterization and pharmacological evaluation
2016 - AKKARI, ALESSANDRA C.S.; PAPINI, JULIANA Z.B.; GARCIA, GABRIELLA K.; FRANCO, MARGARETH K.K.D.; CAVALCANTI, LEIDE P.; GASPERINI, ANTONIO; ALKSCHBIRS, MELISSA I.; YOKAICHYIA, FABIANO; PAULA, ENEIDA de; TOFOLI, GIOVANA R.; ARAUJO, DANIELE R. de
In this study,we reported the development and the physico-chemical characterization of poloxamer 407 (PL407) and poloxamer 188 (PL188) binary systems as hydrogels for delivering ropivacaine (RVC), as drug model, and investigate their use in infiltrative local anesthesia for applications on the treatment of post-operative pain. We studied drug-micelle interaction and micellization process by light scattering and differential scanning calorimetry (DSC), the sol-gel transition and hydrogel supramolecular structure by small-angle-X-ray scattering (SAXS) andmorphological evaluation by Scanning ElectronMicroscopy (SEM). In addition,we have presented the investigation of drug release mechanisms, in vitro/in vivo toxic and analgesic effects. Micellar dimensions evaluation showed the formation of PL407-PL188 mixed micelles and the drug incorporation, as well as the DSC studies showed increased enthalpy values for micelles formation after addition of PL 188 and RVC, indicating changes on self-assembly and the mixed micelles formation evoked by drug incorporation. SAXS studies revealed that the phase organization in hexagonal structure was not affected by RVC insertion into the hydrogels,maintaining their supramolecular structure. SEManalysis showed similar patterns after RVC addition. The RVC release followed the Higuchi model, modulated by the PL final concentration and the insertion of PL 188 into the system. Furthermore, the association PL407-PL188 induced lower in vitro cytotoxic effects, increased the duration of analgesia, in a single-dose model study, without evoking in vivo inflammation signs after local injection.
Synchrotron powder diffraction study of cements pastes
2015 - GARCEZ, E.O.; ALDRIGE, L.P.; RAVEN, M.; GATES, W.P.; COLLINS, F.; FRANCO, M.; YOKAICHIYA, F.
Clonidine complexation with hydroxypropyl-beta-cyclodextrin: From physico-chemical characterization to in vivo adjuvant effect in local
2016 - BRAGA, M.A.; MARTINI, M.F.; PICKHOLZ, M.; YOKAICHIYA, F.; FRANCO, MARGARETH K.K.D.; CABEÇA, L.F.; GUILHERME, V.A.; SILVA, C.M.G.; LIMIA, C.E.G.; PAULA, E. de