Marcílio S S Cunha-Filho

University of Brasília, Brasília, Federal District, Brazil

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Publications (19)22.62 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies have shown that the antifungal itraconazole (ITZ), when in associations with benznidazole (BNZ), is a potential treatment for Chagas disease. Therefore, the objective of the present study was to evaluate the compatibility of ITZ with BNZ and with selected pharmaceutical excipients. Differential scanning calorimetry (DSC), derivative thermogravimetry (DTG), Fourier transform infrared spectroscopy (FTIR), optical microscopy and kinetic analyses under isothermal conditions were performed. The results showed thermal interactions between ITZ and the excipients hydroxypropyl methylcellulose and polyvinylpyrrolidone. The FTIR data together with complementary tests revealed signs of drug decomposition in the presence of these materials. Thus, these excipients were considered incompatible with ITZ and should be avoided in solid dosage forms containing this drug. Moreover, it was found that associations between ITZ and BNZ are potentially unstable. Therefore, it is necessary to develop a pharmaceutical dosage form that avoids the processing of these drugs together and allows a stable pharmaceutical formulation to be obtained.
    Thermochimica Acta 01/2014; 575:29–33. · 1.99 Impact Factor
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    Marcílio S S Cunha-Filho, Ramón Martínez-Pacheco, Mariana Landin
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    ABSTRACT: In this work, the effects of several technological factors on the stability of β-lapachone (βLAP) in solution and in the solid state were investigated. The effects of relative humidity and light on the stability of βLAP in the solid state were studied. Samples were characterized by liquid chromatography, thermal analysis, X-ray powder diffraction and optical microscopy. In solution, the effects of light conditions and additives (cyclodextrins) were also evaluated. Molecular modelling was used to support the degradation mechanism involved. Additionally, the pH stability profile of βLAP was established. The synergism of relative humidity and light promoted degradation of βLAP in the solid state, with important consequences for the physical and chemical characteristics of the drug after storage. Random methyl-β-cyclodextrin was able to protect the drug against the hydrolytic process in darkness. However, it accelerated the drug decomposition by photolysis in light conditions. According to the pH stability profile, βLAP undergoes an alkaline hydrolysis, its maximum stability pH being over the range 2-4. These studies provide useful information regarding the optimal storage conditions and formulations of βLAP.
    The Journal of pharmacy and pharmacology. 06/2013; 65(6):798-806.
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    ABSTRACT: This work evaluated the potential of Pluronics (varieties F127 and P123) in combination with solubilizing agents to be used as syringeable in situ gelling depots of intratumoral β-lapachone (βLAP). Pluronic dispersions prepared at various concentrations in the absence and the presence of ethanol and randomly methylated β-cyclodextrin (RMβCD) were characterized regarding their rheological properties, drug solubilization capacity, and in vitro release. Pluronic F127 (18-23%) formulations combined high ability to solubilize βLAP (enhancement solubility factor up to 50), adequate gel temperature range (over 25 °C), and gel strength at 37 °C enough to guarantee the permanence of the formulation in the administration site for a period of time. βLAP release rate was finely tuned by the concentration of the polymer and the addition of RMβCD (diffusion coefficient ranging between 9 and 69 μg · cm(-2)). The ethanol increases βLAP release rate but simultaneously led to weak gels. This paper shows that βLAP formulations involving temperature-reversible Pluronic gels may be suitable for intratumoral drug delivery purposes.
    The Scientific World Journal 01/2012; 2012:126723. · 1.73 Impact Factor
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    ABSTRACT: Benznidazole (BNZ) is the primary chemotherapeutic agent for treating Chagas' disease; however, its poor water solubility and irregular oral absorption lead to the treatment failure in the chronic phase. The aim of this work was to investigate the utility of the polymer hydroxypropyl methylcellulose (HPMC) in controlling the release of BNZ from solid inclusion complexes with cyclodextrin to overcome the problem of its bioavailability. Preliminary studies of solubility were conducted in solution using selected β-cyclodextrin derivatives according to an experimental mixture design. The best cyclodextrin composition was used to produce solid-state systems by kneading in the presence or absence of HPMC. The formulations were characterized by different physico-chemical techniques, including the dissolution rate. Hydroxypropyl-β-cyclodextrin (HPβCD) produced the greatest improvement in drug solubility and was selected for the development of solid systems. Assays confirmed the production of true inclusion complexes between BNZ and HPβCD. The dissolution rate of the BNZ-HPβCD system was markedly increased, while the presence of HPMC retarded drug release. An optimal formulation obtained by the combination of kneading systems developed in appropriate ratios could be a promising drug delivery system with a prolonged therapeutic effect coupled with more balanced bioavailability. The produced systems present interesting perspectives for Chagas' therapy.
    Pharmaceutical Development and Technology 12/2011; · 1.33 Impact Factor
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    ABSTRACT: The purpose of this study was to investigate the polymorphism and compatibility of benznidazole (BNZ), a drug used in the treatment of Chagas disease. This drug was subjected to a polymorphic screen using a number of solvents and precipitation procedures to explore the possible existence of different crystal structures of BNZ. The compatibility of BNZ with selected pharmaceutical excipients was evaluated in binary mixtures, in a ratio of 1:1 (w/w). These results were then analyzed with a variety of techniques, including differential scanning calorimetry, Fourier transform infrared spectroscopy, and X-ray powder diffractometry. No polymorphic forms of BNZ were detected despite some observed changes in the DSC profile. The thermal data indicate interaction of the drug with excipients hydroxyethylcellulose, polyethylene glycol, and hydroxypropyl-β-cyclodextrin. Additional studies using infrared spectroscopy confirm the incompatibility of BNZ with only the polyethylene glycol. This excipient should not be used in the development of solid dosage forms containing BNZ. KeywordsBenznidazole–Compatibility–Differential scanning calorimetry–Fourier transform infrared spectroscopy–Polymorphism–X-ray powder diffractometry
    Journal of Thermal Analysis and Calorimetry 12/2011; 106(3):819-824. · 1.98 Impact Factor
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    Marcílio S S Cunha-Filho, Ramón Martínez-Pacheco, Mariana Landin
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    ABSTRACT: β-lapachone (βLAP) is obtained from natural resources with promising preliminary results against the etiologic agent of Chagas disease. βLAP activity is associated with generation of free radical and inhibition of nucleic acids and protein synthesis leading an outstanding antichagasic action. Low water solubility and large therapeutic doses constitute the main problems to overcome in the development of dosage forms of this drug. The purpose of the present research was to enhance the limited dissolution rate of βLAP by promoting the spontaneous crystalline growth of βLAP on the surface of an inert excipient. Physicochemical characterization of the particles was carried out as well as the drug dissolution rate. Drug adsorbed particles were compared to the drug as supplied and its physical mixtures with the inner excipient. The utility of the βLAP adsorbed particles in the development of tablets obtained by direct compression were also evaluated. Particles produced by spontaneous crystalline growth of βLAP on microcrystalline cellulose (MCC) hydrophilic surface showed mean diameters between 55-65 µm and fast drug dissolution rate (90% drug dissolved at 50 min). Neither physical nor chemical instability of the drug were detected after the drug adsorption procedure. The compression process does not extensively deteriorate the dissolution behaviour of the systems when an adequate compression pressure is used. Surface adsorption technique offers a simple way to produce βLAP powder and tablets with improved dissolution rate for oral administration.
    Drug Development and Industrial Pharmacy 11/2011; 38(7):866-71. · 1.54 Impact Factor
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    ABSTRACT: The purpose of this work was to study the chemical stability of the new antitumoral β-lapachone (βLAP) to determine the degradation pathway/s of the molecule and the degradation kinetics in addition to identifying several degradation products. Samples of βLAP in solution were stored under conditions of darkness and illumination at 40°C at which the pseudo-first order rate constants for the βLAP degradation were determined. Furthermore, drug degraded solutions were concentrated and purified using Sephadex LH-20 and preparative thin-layer chromatography and degradation products were identified by nuclear magnetic resonance spectroscopy. The results revealed that βLAP shows two different degradation routes: hydrolysis in the dark and photolysis under the light. The βLAP exposure to light accelerated the drug degradation about 140 fold, compared with the samples stored in the absence of light. The hydrolysis produced hydroxylapachol as the main degradation product. The photolysis yielded phthalic acid, 6-hydroxy-3methylene-3H-isobenzofuran-1-one and a benzomacrolactone together with a complex mixture of other phthalate-derivatives such as 2-(2-carboxy-acetyl)-benzoic acid. This study provides useful information for the development of βLAP dosage forms, their storage, manipulation and quality control.
    The Journal of pharmacy and pharmacology. 09/2011; 63(9):1156-60.
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    ABSTRACT: Benznidazole (BNZ), the primary chemotherapy agent used to treat Chagas disease, has poor aqueous solubility, which results in low bioavailability. The purpose of this work was to develop stable effervescent tablets using an inclusion complex of BNZ with cyclodextrin (CD). In the first phase, different CDs were evaluated according to their ability to improve the aqueous solubility of BNZ. Then, inclusion complexes of BNZ in the solid state were produced by the kneading method and the complexes were evaluated using several physical-chemical assays. Finally, effervescent tablets were prepared according to a complete 3(2) factorial design. The effects of the concentration of CD and effervescent mixture on the dissolution rate and physical stability of tablets were evaluated. Hydroxypropyl-β-cyclodextrin produced the greatest improvement in the aqueous solubility of BNZ, almost 20-times greater than the water system. Solid systems produced with BNZ and CD showed physical-chemical interactions and increased the drug dissolution rate, suggesting the formation of a true solid inclusion complex. Moreover, the effervescent matrix of the tablets was effective in improving the dissolution behaviour of BNZ complexed with CD. Effervescent tablets produced using an inclusion complex of BNZ with CD suggest a possible improvement in the bioavailability of BNZ, and this could represent a relevant advance in Chagas therapy.
    The Journal of pharmacy and pharmacology. 06/2011; 63(6):786-93.
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    ABSTRACT: The aim of this study was to investigate the feasibility of a co-processing technique for improving the manufacturing properties of Maytenus ilicifolia (Schrad.) Planch., Celastraceae, and Cassia angustifolia Vahl, Fabaceae, extracts in order to obtain tablets containing a high dose of such extracts. An experimental mixture design was used to optimise the formulation composition. Flowability parameters, such as compressibility index, time flow and angle of repose, were determined. Additional important industrial parameters, such as granulometry, bulk density and moisture stability, were also studied. The results demonstrated that co-processing technique was able to improve the flowability of vegetal extracts, making these materials suitable for a direct compression process. The contour plots revealed that formulations with a higher amount of lactose produced the best flow results as well as a larger particle size and a greater bulk density. Tablets from co-processed extracts containing lactose as majority diluent showed appropriate physical-chemical characteristics and presented a more stable moisture sorption behaviour compared to commercial gelatine capsules.
    Revista Brasileira de Farmacognosia 06/2011; 21(3):510-517. · 0.68 Impact Factor
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    ABSTRACT: Benznidazole (BNZ) is traditionally used to treat Chagas disease. Despite its common use, BNZ has a poor water solubility and a variable bioavailability. The purpose of this study was to prepare BNZ microcrystals by solvent change precipitation and to study the effects of BNZ micronisation on therapeutic efficiency using a murine model of Chagas disease. The solvent change precipitation procedure was optimised in order to obtain stable and homogeneous particles with a small particle size, high yield and fast dissolution rate. The thermal and crystallographic analysis showed no polymorphic change in the microcrystals, and microscopy confirmed a significant reduction in particle size. A marked improvement in the drug dissolution rate was observed for micronised BNZ particles and BNZ tablets in comparison with untreated BNZ and commercial Rochagan. In vivo studies showed a significant increase in the therapeutic efficacy of the BNZ microparticles, corroborating the dissolution results.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 03/2011; 78(3):377-84. · 3.15 Impact Factor
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    ABSTRACT: Currently, benznidazole (BNZ) is a unique therapeutic alternative available in Brazil to treat Chagas disease. Despite its traditional medical use, little is known about the chemical nature of this drug. A detailed study of the physicochemical properties of BNZ was performed using multiple assays. Thermal, diffractometric, morphological and reological drug profiles were obtained. The partition coefficient and solubility results allowed this drug to be classified as a class IV drug according to the biopharmaceutical classification system. This information will be useful for the development of more effective BNZ formulations and for establishing the quality profile of BNZ.
    Química Nova 12/2009; 33(8):1714-1719. · 0.74 Impact Factor
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    M. S.S. Cunha-Filho, L. C.L. Sá-Barreto
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    ABSTRACT: As ciclodextrinas (CDs) constituem uma nova classe de excipientes farmacêuticos com capacidade para formar complexos de inclusão reversíveis com moléculas apolares. A habilidade das CDs em encapsular fármacos tem conseguido melhoras na biodisponibilidade, estabilidade e segurança de inúmeras fórmulas farmacêuticas atualmente comercializadas. Esta revisão bibliográfica compila os principais procedimentos empregados para a obtenção de complexos de inclusão em solução e em estado sólido utilizando CDs, discutindo seus diferentes aspectos. As técnicas utilizadas para caracterização e controle são analisadas criticamente quanto a suas aportações e limitações. Os aspectos relacionados à sua utilização pela indústria farmacêutica também são abordados. Palavras-chave: ciclodextrinas; excipiente farmacêutico; complexo de inclusão; biodisponibilidade
    Revista de Ciências Farmacêuticas Básica e Aplicada. 01/2009;
  • Marcílio S S Cunha-Filho, Ramón Martínez-Pacheco, Mariana Landín
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    ABSTRACT: beta-Lapachone [betaLAP] is a novel antitumor drug, which was recently on clinical trials with promising preliminary results. Problems derived from its low water solubility, its instability in solution and its high therapeutic dose constitute some challenges for pharmaceutical researchers. The purpose of the present work is to enhance the limited dissolution rate of betaLAP by the design of particles using a solvent change precipitation process. The procedure induces the spontaneous crystalline growth of the betaLAP in the presence of a stabilizing polymer (Hydroxypropylmethylcellulose) that limits the size of the particles generated. Physicochemical characterization of microparticles and the betaLAP dissolution rate was carried out. The utility of the betaLAP microcrystals in the development of tablets with adequate dissolution properties was also stated. The procedure was optimized in order to obtain stable and homogeneous particles with a small mean particle size (approximately 3 microm) and a narrow particle size distribution. There were no differences between the drying methods evaluated (in an oven and freeze-drying) with regard to particle morphology or dissolution behaviour, which is almost instantaneous. Tablets having suitable mechanical properties were produced by dry granulation prior to compression. The compression process did not compromise betaLAP dissolution characteristics.
    European Journal of Pharmaceutics and Biopharmaceutics 03/2008; 69(3):871-7. · 3.83 Impact Factor
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    ABSTRACT: RESUMO. O presente trabalho investigou pela primeira vez a atividade biológica e a toxicidade aguda de Vitex gardneriana Schauer, planta de utilização popular encontrada no sertão nordestino do Brasil. A toxi- cidade aguda, determinada por via oral e intraperitoneal, e diferentes atividades farmacológicas (antimi- crobiana, anti-inflamatória, analgésica e hipnótica) foram pesquisadas utilizando soluções aquosas dos ex- tratos brutos das cascas do caule e das folhas. Não se detectou sinais de toxicidade em nenhuma das doses testadas (250-2000 mg/kg). Foram encontrados relevantes efeitos farmacológicos nos extratos das folhas, que apresentaram ações anti-edematogênicas, antinociceptivas e sedantes. Os resultados encontrados cor- roboram a utilização popular de V. gardneriana e sugerem um excelente potencial terapêutico. SUMMARY. "Preliminary Assay of Biological Activity and Acute Toxicity of Vitex gardneriana Schauer (Ver- benaceae)". The biological activity and the acute toxicity of Vitex gardneriana Schauer, a medicinal plant with popular use, were investigated. Acute toxicity after oral and intraperitoneal administration, antimicrobial, anti-in- flammatory, analgesic and hypnotic tests were carried out using leaves and stem bark aqueous extracts. No signs of toxicity were found in the dosage range tested (250-2000 mg/kg). Important pharmacological effects were found for leaves extract, which presented anti-edematogenic, anti-nociceptive and sedative actions. These results corroborate the popular use of V. gardneriana and point out a promising therapeutic potential.
    01/2008;
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    ABSTRACT: THE CONFORMATION OF THE TITLE COMPOUND [SYSTEMATIC NAME: N-benzyl-2-(2-nitro-imidazol-1-yl)acetamide], C(12)H(12)N(4)O(3), can be described in terms of the relative orientation of three planar fragments, the imidazol group (A), benzyl group (B), and the acetamide fragment (C), with corresponding dihedral angles: A/C = 88.17 (4), B/C = 67.12 (5) and A/B = 21.11 (4)°. The crystal packing is enhanced by a network of strong inter-molecular N-H⋯O hydrogen bonds.
    Acta Crystallographica Section E Structure Reports Online 01/2008; 64(Pt 3):o634. · 0.35 Impact Factor
  • Marcílio S S Cunha-Filho, Ramón Martínez-Pacheco, Mariana Landín
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    ABSTRACT: The objective of the present study was to evaluate the compatibility of the beta-lapachone (betaLAP), an antitumoral drug in clinical phase, with pharmaceutical excipients of common use including diluents, binders, disintegrants, lubricants and solubilising agents. Differential scanning calorimetry (DSC) was used for a first screening to find small variations in peak temperatures and/or their associated enthalpy for six drug/excipient combinations (magnesium stearate, sodium estearyl fumarate, dicalcium phosphate dihydrate, mannitol, randomized methyl-beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin), which indicate some degree of interaction. Additional studies using Fourier transformed infrared spectroscopy (FTIR), optical microscopy (OM) and heating-cooling DSC (HC-DSC) confirmed the incompatibility of betaLAP with magnesium stearate and dicalcium phosphate dihydrate. Those excipients should be avoided in the development of solid dosage forms.
    Journal of Pharmaceutical and Biomedical Analysis 12/2007; 45(4):590-8. · 2.95 Impact Factor
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    ABSTRACT: The purpose of this research was to explore the utility of beta cyclodextrin (betaCD) and beta cyclodextrin derivatives (hydroxypropyl-beta-cyclodextrin [HPbetaCD], sulfobutylether-beta-CD [SBbetaCD], and a randomly methylated-beta-CD [RMbetaCD]) to form inclusion complexes with the antitumoral drug, beta-lapachone (betaLAP), in order to overcome the problem of its poor water solubility. RMbetaCD presented the highest efficiency for betaLAP solubilization and was selected to develop solid-state binary systems. Differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), Fourier transform infrared (FTIR) and optical and scanning electron microscopy results suggest the formation of inclusion complexes by both freeze-drying and kneading techniques with a dramatic improvement in drug dissolution efficiency at 20-minute dissolution efficiency (DE(20-minute) 67.15% and 88.22%, respectively) against the drug (DE(20-minute) 27.11%) or the betaCD/drug physical mixture (DE(20-minute) 27.22%). However, the kneading method gives a highly crystalline material that together with the adequate drug dissolution profile make it the best procedure in obtaining inclusion complexes of RMbetaCD/betaLAP convenient for different applications of betaLAP.
    AAPS PharmSciTech 02/2007; 8(3):E60. · 1.58 Impact Factor
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    ABSTRACT: The most remarkable aspect of the crystal structure of the title compound (systematic name: 3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione), C15H14O3, is that a π-stacking inter­action is present between the two naphthalene ring systems of symmetry-related mol­ecules. Apart from these π–π inter­actions, different mol­ecules are held together by weak C—H⋯O hydrogen-bonding inter­actions.
    ChemInform 01/2007; 38(2).
  • Acta Crystallographica Section C Crystal Structure Communications 09/2006; 62(Pt 8):o473-5. · 0.78 Impact Factor

Publication Stats

64 Citations
22.62 Total Impact Points

Institutions

  • 2012–2014
    • University of Brasília
      • Faculty of Health Sciences
      Brasília, Federal District, Brazil
  • 2011
    • Universidade Federal de Mato Grosso (UFMT)
      • Institutos de Ciências da Saúde (ICS)
      Cuiabá, Estado de Mato Grosso, Brazil
  • 2009–2011
    • Universidade Federal de Mato Grosso do Sul
      Campo Grande, Estado de Mato Grosso do Sul, Brazil
  • 2008–2011
    • Universidade Federal de Ouro Preto
      • School of Pharmacy
      Ouro Preto, Estado de Minas Gerais, Brazil
  • 2006–2008
    • University of Santiago de Compostela
      • • Departamento de Farmacia y Tecnología Farmacéutica
      • • Facultad de Farmacia
      Santiago de Compostela, Galicia, Spain