RESUMO
BACKGROUND: Benznidazole and nifurtimox are effective drugs used to treat Chagas' disease; however, their administration in patients in the chronic phase of the disease is still limited, mainly due to their limited efficacy in the later chronic stage of the disease and to the adverse effects related to these drugs. OBJECTIVES: To evaluate the effect of low doses of nanoformulated benznidazole using a chronic model of Trypanosoma cruzi Nicaragua infection in C57BL/6J mice. METHODS: Nanoformulations were administered in two different schemes: one daily dose for 30 days or one dose every 7 days, 13 times. RESULTS: Both treatment schemes showed promising outcomes, such as the elimination of parasitaemia, a reduction in the levels of T. cruzi-specific antibodies and a reduction in T. cruzi-specific IFN-γ-producing cells, as well as an improvement in electrocardiographic alterations and a reduction in inflammation and fibrosis in the heart compared with untreated T. cruzi-infected animals. These results were also compared with those from our previous work on benznidazole administration, which was shown to be effective in the same chronic model. CONCLUSIONS: In this experimental model, intermittently administered benznidazole nanoformulations were as effective as those administered continuously; however, the total dose administered in the intermittent scheme was lower, indicating a promising therapeutic approach to Chagas' disease.
Assuntos
Doença de Chagas , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Animais , Doença de Chagas/tratamento farmacológico , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Nicarágua , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêuticoRESUMO
Numerous films with a dissolved or dispersed active principle within a polymeric matrix have been described in literature. However, the incorporation of solid crystals into the films may influence several relevant properties. Additionally, it has been reported that different polymeric matrices lead to films presenting a different performance. The aim of this work was to evaluate the effect of the combination of chitosan with carrageenan (κ-, λ-, and ι-) as matrices, and of the miconazole nitrate incorporation method, on the films behavior. Mechanical properties, drug release and antifungal activity were evaluated. The state of the drug in the films was analyzed by different techniques. Films showed a homogeneous surface and a thermal protective effect on the drug. The combination of chitosan and λ-carrageenan leads to films with the highest values of tensile and mucoadhesive strength. Films with solubilized drug displayed slightly higher elongation at break, tensile and mucoadhesive strength and faster drug release than those with suspended miconazole nitrate. However, no differences were found regarding the antifungal activity of the different formulations including time-to-kill curves.
Assuntos
Antifúngicos/administração & dosagem , Carragenina/administração & dosagem , Química Farmacêutica/métodos , Quitosana/administração & dosagem , Miconazol/administração & dosagem , Adesividade , Administração Bucal , Antifúngicos/química , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Carragenina/química , Quitosana/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Miconazol/química , Resistência à TraçãoRESUMO
Oral candidiasis is the most common opportunistic infection affecting patients with the human immunodeficiency virus. Miconazole buccal tablets or miconazole gel are approved for the treatment of oropharyngeal candidiasis. However, buccal films present more flexibility and also offer protection for the wounded mucosa, reducing pain. Due to their small size and thickness, buccal films may improve patients' compliance, compared to tablets. Additionally, they may increase the relatively short residence time on the mucosa of oral gels, which are easily removed by saliva. Polymeric films loaded with miconazole nitrate were prepared by a casting/solvent evaporation methodology using chitosan, carbopol, gelatin, gum arabic, and alginate to form the polymeric matrices. The morphology of films was investigated by scanning electron microscopy; interactions between polymers were analyzed by infrared spectroscopy and drug crystallinity by differential thermal analysis and X-ray diffraction. Films were characterized in terms of thickness, folding endurance, tensile properties, swelling, adhesiveness, and drug release. Finally, the antifungal activity against cultures of the five most important fungal opportunistic pathogens belonging to Candida genus was investigated. The more appropriate formulations were those based on chitosan-gelatin and chitosan-carbopol which showed good mechanical properties and adhesiveness, a relative low swelling index, improved drug release, and showed better in vitro activity against Candida cultures than miconazole nitrate raw material. Thus, it will be possible to produce a new pharmaceutical form based on polymeric films containing chitosan and miconazole nitrate, which could be loaded with low drug concentration producing the same therapeutic effect against Candida cultures.
Assuntos
Antifúngicos/química , Adesividade , Química Farmacêutica , Miconazol , Polímeros , Difração de Raios XRESUMO
In this work, chitosan films were prepared by a casting/solvent evaporation methodology using pectin or hydroxypropylmethyl cellulose to form polymeric matrices. Miconazole nitrate, as a model drug, was loaded into such formulations. These polymeric films were characterized in terms of mechanical properties, adhesiveness, and swelling as well as drug release. Besides, the morphology of raw materials and films was investigated by scanning electron microscopy; interactions between polymers were analyzed by infrared spectroscopy and drug crystallinity studied by differential scanning calorimetry and X-ray diffraction. In addition, antifungal activity against cultures of the five most important fungal opportunistic pathogens belonging to Candida genus was investigated. Chitosan:hydroxypropylmethyl cellulose films were found to be the most appropriate formulations in terms of folding endurance, mechanical properties, and adhesiveness. Also, an improvement in the dissolution rate of miconazole nitrate from the films up to 90% compared to the non-loaded drug was observed. The in vitro antifungal activity showed a significant activity of the model drug when it is loaded into chitosan films. These findings suggest that chitosan-based films are a promising approach to deliver miconazole nitrate for the treatment of candidiasis.
Assuntos
Candidíase Bucal/tratamento farmacológico , Quitosana , Sistemas de Liberação de Medicamentos , Derivados da Hipromelose/farmacologia , Miconazol , Adesividade , Administração Bucal , Antidiarreicos/química , Antidiarreicos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Quitosana/química , Quitosana/farmacologia , Composição de Medicamentos , Humanos , Miconazol/química , Miconazol/farmacologia , Microscopia Eletrônica de Varredura/métodos , Pectinas/química , Pectinas/farmacologia , Polímeros/farmacologia , Difração de Raios X/métodosRESUMO
Benznidazole (BZL) is the drug of choice for the treatment of Chagas' disease, a neglected parasitic infection. It is poorly soluble in water, which may have a direct impact into its bioavailability. Thus, the aim of this study was to evaluate the impact of stoichiometric and non-stoichiometric BZL-cyclodextrins (CDs) complexes on the bioavailability of BZL. The interaction of BZL with the CDs was investigated using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X-ray diffractometry (XRD), phase solubility and dissolution studies. The oral bioavailability of BZL from these complexes was examined in rats. Both BZL solubility and dissolution increased by CD complexation. The inclusion complexes were found to improve the dissolution rate of BZL by 4.3-fold in comparison with BZL alone. Complexation of BZL with CDs derivatives increased its plasma concentrations when fed to rats, with AUC0-5 values increasing up to 3.7-fold and Cmax increasing 2.5-fold in comparison with BZL alone. It should be note that a remarkable increase in these parameters was observed in the case of the non-stoichiometric complexes. Thus, these CDs complexes could be used to efficiently deliver BZL in patients suffering from Chagas' disease.