Carla Vitorino
University of Coimbra
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Publication
Featured researches published by Carla Vitorino.
Colloids and Surfaces B: Biointerfaces | 2011
Carla Vitorino; Filomena A. Carvalho; António J. Almeida; João J. Sousa; Alberto A. C. C. Pais
This study aimed to investigate the role of different factors affecting the size of solid lipid nanoparticles (SLN), prepared by the emulsification-solvent evaporation method. A double factorial design was conducted so as to cover a wide range of sizes, highlighting zones with different behaviour with respect to changes in the controlled variables: lipid concentration, solvent:lipid ratio and emulsifier concentration. The solvent:lipid ratio constituted the main factor influencing particle size. Increasing the amount of solvent induced a decrease in the size. This was a general trend, essentially independent from solvent and lipid type. The amount of emulsifier had a non-trivial impact on size, depending on whether systems were located below, above or close to the optimal surface coverage. The amount of lipid had a limited influence upon particle size, being more relevant for lower lipid concentrations. An optimal formulation was selected for intermediate levels of the three variables. Sonication reduced both particle size and polydispersity. These particles were also tested as drug carriers using simvastatin as a model of lipophilic drug. SLN were able to entrap a high amount of simvastatin, with little effect upon size and zeta potential, constituting a promising carrier for lipophilic drugs.
Journal of Controlled Release | 2013
Carla Vitorino; João A. S. Almeida; L. M. Gonçalves; António J. Almeida; João J. Sousa; Alberto A. C. C. Pais
Co-encapsulation of drugs directed at commonly associated diseases provides a convenient means for administration, especially if transdermally delivered. In this work, a comprehensive study for the co-encapsulation of drugs with a differential lipophilicity, olanzapine and simvastatin, and their transdermal delivery in a formulation containing nanostructured lipid carriers (NLC) is presented. Focus is given to the evaluation of a strategy in which NLC and chemical permeation enhancers are combined. It comprises in vitro, in silico and cellular viability approaches. The optimization and rationalization of the systems are carried out using a two-step factorial design. It is shown that the external medium in the NLC dispersion strongly influences permeation. It is also seen that the use of NLC determines a synergistic effect with selected permeation enhancers, thus promoting marked flux enhancement ratios (48 and 21, respectively for olanzapine and simvastatin) relative to the drugs in solution. The developed formulations can be considered non-irritant. A correlation between enhancer positioning in a lipid bilayer, partially governed by a H-bonding phenomenon, and enhancement effect is suggested from molecular dynamics studies and experimental observations.
European Journal of Pharmaceutics and Biopharmaceutics | 2014
Carla Vitorino; António J. Almeida; João Marcelo de Castro e Sousa; Isabelle Lamarche; Patrice Gobin; Sandrine Marchand; William Couet; Jean-Christophe Olivier; Alberto A. C. C. Pais
This work aimed at designing a formulation based on nanostructured lipid carriers (NLC) for transdermal co-administration of olanzapine and simvastatin, using passive and active strategies in a combined in vitro/in vivo development approach. NLC were prepared by two distinct methods, namely solvent emulsification-evaporation (SE/E) and high pressure homogenization (HPH). HPH was selected on the basis of a better performance in terms of drug loading and in vitro permeation rate. Several mathematical models were used to elucidate the release mechanisms from lipid nanoparticles. In vitro release kinetics was shown to be driven by diffusion, but other mechanisms were also present, and supported the feasibility of using NLC for sustained drug delivery. The in vitro skin studies showed that the chemical penetration enhancers, limonene and ethanol, added to the NLC formulations, promoted a synergistic permeation enhancement of both drugs, with olanzapine exhibiting a higher permeation than simvastatin. Transdermal administration to rats resulted in steady-state levels reached at around 10h and maintained for 48h, again with olanzapine exhibiting a better permeation rate. The pharmacokinetic parameters indicated that the NLC dispersion displayed a better in vivo performance than the gel, which was consistent with the in vitro results. These differences were, however, negligible in the flux values, supporting the use of gel as a final, more convenient, formulation. The in vivo experiments in rats correlated well with in vitro findings and revealed that the combined use of ethanol and limonene, incorporated in the NLC formulation, provided the main driving force for drug permeation. The Dermaroller® pretreatment did not significantly enhance drug permeation, supporting the use of passive methods as suitable for a transdermal delivery system. Furthermore, this work may provide a promising proof-of-concept for further clinical application in the treatment of schizophrenia and associated disorders, combined with dyslipidemia.
Journal of Ethnopharmacology | 2016
Gustavo Costa; João Pinto Ferreira; Carla Vitorino; M. E. Pina; João J. Sousa; Isabel Vitória Figueiredo; Maria Teresa Batista
ETHNOPHARMACOLOGICAL RELEVANCE A variety of plant polyphenols have been reported to have anti-inflammatory, frequently associated with erythema, edema, hyperplasia, skin photoaging and photocarcinogenesis. Cymbopogon citratus (DC). Stapf (Poaceae) is a worldwide known medicinal plant, used in traditional medicine in inflammation-related conditions. AIM OF THE STUDY In this work, the anti-inflammatory potential of C. citratus infusion (CcI) and its polyphenols as topical agents was evaluated in vivo. MATERIALS AND METHODS The plant extract was prepared and its fractioning led two polyphenol-rich fractions: flavonoids fraction (CcF) and tannins fraction (CcT). An oil/water emulsion was developed with each active (CcI, CcF+CcT and diclofenac), pH and texture having been evaluated. Release tests were further performed using static Franz diffusion cells and all collected samples were monitored by HPLC-PDA. In vivo topical anti-inflammatory activity evaluation was performed by the carrageenan-induced rat paw edema model. RESULTS The texture analysis revealed statistically significant differences for all tested parameters to CcF+CcT, supporting its topical application. Release experiments lead to the detection of the phenolic compounds from each sample in the receptor medium and the six major flavonoids were quantified, by HPLC-PDA: carlinoside, isoorientin, cynaroside, luteolin 7-O-neohesperidoside, kurilesin A and cassiaoccidentalin B. The CcF+CcT formulation prompted to the higher release rate for all these flavonoids. CcI4%, CcI1% and CcF+CcT exhibited an edema reduction of 43.18, 29.55 and 59.09%, respectively. CONCLUSIONS Our findings highlight that CcI, containing luteolin 7-O-neohesperidoside, cassiaoccidentalin B, carlinoside, cynaroside and tannins have a potential anti-inflammatory topical activity, suggesting their promising application in the treatment of skin inflammatory pathologies.
International Journal of Pharmaceutics | 2017
Ana Miranda; María J. Blanco-Prieto; João Marcelo de Castro e Sousa; Alberto A. C. C. Pais; Carla Vitorino
Glioblastoma multiforme (GBM) is the most common primary brain tumour, and the most aggressive in nature. The prognosis for patients with GBM remains poor, with a median survival time of only 1-2 years. The treatment failure relies on the development of resistance by tumour cells and the difficulty of ensuring that drugs effectively cross the dual blood brain barrier/blood brain tumour barrier. The advanced molecular and genetic knowledge has allowed to identify the mechanisms responsible for temozolomide resistance, which represents the standard of care in GBM, along with surgical resection and radiotherapy. Such resistance has motivated the researchers to investigate new avenues for GBM treatment intended to improve patient survival. In this review, we provide an overview of major obstacles to effective treatment of GBM, encompassing biological barriers, cancer stem cells, DNA repair mechanisms, deregulated signalling pathways and autophagy. New insights and potential therapy approaches for GBM are also discussed, emphasizing localized chemotherapy delivered directly to the brain, immunotherapy, gene therapy and nanoparticle-mediated brain drug delivery.
Analytical Methods | 2013
Carla Vitorino; João J. Sousa; Alberto A. C. C. Pais
In the present work, a rapid reversed phase high performance liquid chromatography (RP-HPLC) method was developed for the simultaneous determination of simvastatin, including the lactone prodrug (SV) and the respective active hydroxy acid form, simvastatin acid (SVA) and olanzapine (OL) in a formulation containing co-encapsulating-nanostructured lipid carriers (Combo-NLC). The desired chromatographic separation was achieved on a Phenomenex Luna Phenyl-Hexyl, 5 μm (150 × 3 mm) column at a temperature of 35 °C, under isocratic conditions using UV detection at 230 nm. The optimized mobile phase consisted of a mixture of ammonium acetate aqueous solution (0.02 M), methanol and acetonitrile (30 : 35 : 35, v/v/v) at a flow rate of 0.8 mL min−1. The linear regression analysis for the calibration curves showed a good linear correlation over the concentration range 0.5–100 μg mL−1, with determination coefficients, R2, exceeding 0.9994 for all three compounds, SVA, SV and OL. The method was shown to be specific, without the interference of NLC components, precise at the intra-day and inter-day levels, as reflected by the relative standard deviation values, lower than 9.014%, accurate with bias not exceeding 15% and characterized by a recovery rate of 100 ± 8%. The limits of detection and quantification were, respectively, 0.07 and 0.22 μg mL−1 for OL, 0.12 and 0.36 μg mL−1 for SV and 0.09 and 0.27 μg mL−1 for SVA. The method was successfully applied for the determination of Combo-NLC entrapment efficiency.
Molecular Pharmaceutics | 2017
Maria Mendes; Sandra C.C. Nunes; J.J. Sousa; Alberto A. C. C. Pais; Carla Vitorino
A monolithic drug-in-NLC-in-adhesive transdermal patch, with a novel design, was developed for codelivery of olanzapine (OL) and simvastatin (SV). Nanostructured lipid carriers (NLC) and enhancers were used as passive strategies, while the pretreatment of the skin with Dermaroller was tested as an active approach. The formulation was optimized for composition in a quality by design basis, in terms of enhancer and adhesive, with focus on permeation behavior, adhesion properties, and cytotoxicity. Propylene glycol promoted the best permeation rate for both drugs, with enhancement ratios of 8.1 and 12.9 for OL and SV, respectively, relative to the corresponding Combo-NLC patch without enhancer. Molecular dynamics results provided a rationale for these observations. The adhesive type displayed an important role in skin permeation, reinforced by the presence of the enhancer. Finally, Dermaroller pretreatment did not promote a significant improvement in permeation, which highlights the role of the combination of NLC with chemical enhancer in the transdermal patch as the main driving force in the process. It is also observed that NLC are able to reduce cytotoxicity, especially that associated with SV. This work provides a promising in vitro-in silico basis for a future in vivo development.
International Journal of Pharmaceutics | 2017
Ana Miranda; María J. Blanco-Prieto; João Marcelo de Castro e Sousa; Alberto A. C. C. Pais; Carla Vitorino
Tailored nanocarriers have gained huge research focus for brain drug delivery, aimed at combating several neuro-oncological conditions, such as the glioblastoma multiforme (GBM). The progress of knowledge on the pathogenesis of GBM has allowed identifying the major hurdles for efficient treatment, encompassing biological interfaces (blood-brain barrier and blood-brain tumour barrier), specificities of tumour microenvironment, as well as both bulk and glioma stem cell subpopulations. These findings provided new insights into the molecular basis of GBM, being a strong driving force behind development of targeted nanomedicines in this area. Diversified nanoparticles have been designed to target GBM surface markers, overexpressed receptors, aberrant genes and signalling pathways, in addition to contemplating barriers targeting strategies. Among the nanocarriers explored, lipid nanoparticles claim important and unique features, including the versatility in promoting both passive and active drug targeting, making them excellent candidates for brain drug delivery and one of the most appealing to overcome the obstacles of the current GBM treatment.
International Journal of Pharmaceutics | 2016
Maria Mendes; Helder T. Soares; Luis G. Arnaut; J.J. Sousa; Alberto A. C. C. Pais; Carla Vitorino
Lipid nanoparticles and their multiple designs have been considered appealing nanocarrier systems. Bringing the benefits of these nanosystems together with conventional coating technology clearly results in product differentiation. This work aimed at developing an innovative solid dosage form for oral administration based on tableting nanostructured lipid carriers (NLC), coated with conventional polymer agents. NLC dispersions co-encapsulating olanzapine and simvastatin (Combo-NLC) were produced by high pressure homogenization, and evaluated in terms of scalability, drying procedure, tableting and performance from in vitro release, cytotoxicity and intestinal permeability stand points. Factorial design indicated that the scaling-up of the NLC production is clearly feasible. Spray-drying was the method selected to obtain dry particles, not only because it consists of a single step procedure, but also because it facilitates the coating process of NLC with different polymers. Modified NLC formulations with the polymers allowed obtaining distinct release mechanisms, comprising immediate, delayed and prolonged release. Sureteric:Combo-NLC provided a low cytotoxicity profile, along with a ca. 12-fold OL/3-fold SV higher intestinal permeability, compared to those obtained with commercial tablets. Such findings can be ascribed to drug protection and control over release promoted by NLC, supporting them as a versatile platform able to be modified according to the intended needs.
Future Medicinal Chemistry | 2018
Ana Miranda; Tânia F.G.G. Cova; João Marcelo de Castro e Sousa; Carla Vitorino; Alberto A. C. C. Pais
The integrated in silico-in vitro-in vivo approaches have fostered the development of new treatment strategies for glioblastoma patients and improved diagnosis, establishing the bridge between biochemical research and clinical practice. These approaches have provided new insights on the identification of bioactive compounds and on the complex mechanisms underlying the interactions among glioblastoma cells, and the tumor microenvironment. This review focuses on the key advances pertaining to computational modeling in glioblastoma, including predictive data on drug permeability across the blood-brain barrier, tumor growth and treatment responses. Structure- and ligand-based methods have been widely adopted, enabling the study of dynamic and evolutionary aspects of glioblastoma. Their potential applications as predictive tools and the advantages over other well-known methodologies are outlined. Challenges regarding in silico approaches for predicting tumor properties are also discussed.