RESUMO
The aim of this study was to investigate the influence of the production method and the polymeric carrier on the ability to generate and maintain the supersaturation of a poorly soluble drug in biorelevant medium. The amorphous solid dispersion of sulfamethoxazole, an antibacterial drug, was produced using two different polymers by spray-drying or hot melt extrusion methods. When Eudragit EPO was used, supersaturation was maintained up to 24 h for both techniques at all drug-polymer proportions. However, when Soluplus was employed in hot melt extrusion, a smaller amount of drug was dissolved when compared to the amorphous drug. The proportion of 3:7 drug-Eudragit EPO (w/w) produced by spray-drying presented a higher amount of drug dissolved in supersaturation studies and it was able to maintain the physical stability under different storage conditions throughout the 90-day evaluation. Supersaturation generation and system stability were found to be related to more effective chemical interaction between the polymer and the drug provided by the production method, as revealed by the 1D ROESY NMR experiment. Investigation of drug-polymer interaction is critical in supersaturating drug delivery systems to avoid crystallization of the drug and to predict the effectiveness of the system. Chemical compounds studied in this article: Sulfamethoxazole (PubChem CID: 4539) and Methacrylate copolymer - Eudragit EPO (PubChem CID: 65358).
Assuntos
Preparações Farmacêuticas/química , Polietilenoglicóis/química , Ácidos Polimetacrílicos/química , Polivinil/química , Cristalização , Dessecação , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Interações Medicamentosas , Estabilidade de Medicamentos , SolubilidadeRESUMO
Background: The drug supersaturation in the intestinal lumen for few hours could result in high bioavailability. The goal of this study was the development of a supersaturating drug delivery system containing sulfamethoxazole and trimethoprim at fixed dose combination (sulfamethoxazole:trimethoprim 5:1 w/w). Methods: The amorphous solid dispersions were formed at three different proportions containing 30, 50 and 70% of Eudragit EPO in the formulation. Results: The supersaturation state is formed by the amorphous drugs produced by spray drying technique, and the maintenance of this state is due to the chemical interactions between the drugs and the polymer selected, which was observed in the fluorescence interaction studies realized between the drugs and the polymer. The Formulation containing 70% of the polymer was able to produce and maintain the supersaturated state of both drugs for 24 h. Solid state characterization demonstrated the amorphization of the drugs in the solid dispersion and indicated the hydrogen bond formation responsible for the improvement in the apparent solubility. This formulation presented an improved antibacterial activity when compared to the combination of the drugs. Conclusion: For the first time, a supersaturating drug delivery system was developed to the complementary antibacterial drugs. This ternary formulation is a powerful alternative to improve oral absorption of recognized safety drugs, reducing the dose and consequently the antibiotic resistance emergence.
Assuntos
Antibacterianos/administração & dosagem , Sistemas de Liberação de Medicamentos , Combinação Trimetoprima e Sulfametoxazol/administração & dosagem , Administração Oral , Antibacterianos/química , Antibacterianos/farmacologia , Química Farmacêutica , Portadores de Fármacos/química , Combinação de Medicamentos , Humanos , Polímeros/química , Ácidos Polimetacrílicos/química , Solubilidade , Fatores de Tempo , Combinação Trimetoprima e Sulfametoxazol/química , Combinação Trimetoprima e Sulfametoxazol/farmacologiaRESUMO
A stability-indicating reversed-phase liquid chromatography (LC) method was developed and validated for the determination of lumiracoxib in pharmaceutical formulations. The LC method was carried out on a Synergi fusion C(18) column (150 mmx4.6mm), maintained at 30 degrees C. The mobile phase was composed of phosphoric acid (25 mM; pH 3.0)/acetonitrile (40:60, v/v), run at a flow rate of 1.0mL/min, and detection at 272nm. The chromatographic separation was obtained within 10 min and it was linear in the concentration range of 10-100 microg/mL (r(2)=0.9999). Validation parameters such as the specificity, linearity, precision, accuracy, and robustness were evaluated, giving results within the acceptable range. Stress studies were carried out and no interference of the degradation products was detected. Moreover, the proposed method was successfully applied for the assay of lumiracoxib in pharmaceutical formulations.
Assuntos
Química Farmacêutica/métodos , Diclofenaco/análogos & derivados , Química Farmacêutica/normas , Cromatografia Líquida/métodos , Diclofenaco/análise , Diclofenaco/químicaRESUMO
The physical characterization of active pharmaceutical substances is crucial to the successful development of the final drug product. The different solid forms and variations in the degree of crystallinity can lead to significantly different physical and chemical properties, including color, morphology, stability, dissolution and bioavailability. In the case of omeprazole sodium (OMS), its chemical structures contain a specific number of water molecules (hydrate). The behavior of pharmaceutical hydrates has become the object of increasing attention over the past decade, primarily due to the potential impact of hydrates on the development process and dosage form performance. The present study was designed to characterize and evaluate the crystallinity of omeprazole sodium, dehydrated omeprazole sodium (DOMS) and omeprazole free base (OM) using a variety of techniques including thermal analysis (thermogravimetry/derivative thermogravimetry (TG/DTG) and differential scanning calorimetry (DSC)), diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, scanning electron microscopy (SEM) and X-ray powder diffraction (XRPD). Furthermore, an NMR spectroscopy study was also carried out to clarify the conformation and crystal structure.
Assuntos
Fenômenos Químicos , Inibidores Enzimáticos/química , Temperatura Alta , Omeprazol/química , Análise Espectral , Varredura Diferencial de Calorimetria , Cristalização , Estabilidade de Medicamentos , Ligação de Hidrogênio , Microscopia Eletrônica de Varredura , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Pós , Espectroscopia de Infravermelho com Transformada de Fourier , Estereoisomerismo , Termogravimetria , Titulometria , Água/química , Difração de Raios XRESUMO
A simple, rapid, and sensitive reversed-phase column high-performance liquid chromatographic method was developed and validated to quantify camptothecin (CPT) in polymeric nanocapsule suspensions. The chromatographic separation was performed on a Supelcosil LC-18 column (15 cm x 4.6 mm id, 5 microm) using a mobile phase consisting of methanol-10 mM KH2PO4 (60 + 40, v/v; pH 2.8) at a flow rate of 1.0 mL/min and ultraviolet detection at 254 nm. The calibration graph was linear from 0.5 to 3.0 microg/mL with a correlation coefficient of 0.9979, and the limit of quantitation was 0.35 microg/mL. The assay recovery ranged from 97.3 to 105.0%. The intraday and interday relative standard deviation values were < 5.0%. The validation results confirmed that the developed method is specific, linear, accurate, and precise for its intended use. The current method was successfully applied to the evaluation of CPT entrapment efficiency and drug content in polymeric nanocapsule suspensions during the early stage of formulation development.
Assuntos
Camptotecina/análise , Cromatografia Líquida de Alta Pressão/métodos , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/análise , Antineoplásicos Fitogênicos/normas , Camptotecina/administração & dosagem , Camptotecina/normas , Química Farmacêutica , Cromatografia Líquida de Alta Pressão/normas , Cromatografia Líquida de Alta Pressão/estatística & dados numéricos , Preparações de Ação Retardada , Humanos , Nanocápsulas , Polímeros , Padrões de Referência , Sensibilidade e Especificidade , SuspensõesRESUMO
Inclusion complexes between dexamethasone acetate (DMA), a poorly water soluble drug, and beta-cyclodextrin (betaCD) were obtained to improve the solubility and dissolution rate of this drug. Phase-solubility profile indicated that the solubility of DMA was significantly increased in the presence of betaCD (33-fold) and was classified as A(L)-type, indicating the 1:1 stoichiometric inclusion complexes. Solid complexes prepared by different methods (kneading, coevaporation, freeze drying) and physical mixture were characterized by differential scanning calorimetry, thermogravimetry, infrared absorption and optical microscopy. Preparation methods influenced the physicochemical properties of the products. The dissolution profiles of solid complexes were determined and compared with those DMA alone and their physical mixture, in three different mediums: simulated gastric fluid (pH 1.2), simulated intestinal fluid (pH 7.4) and distilled water. The dissolution studies showed that in all mediums DMA presented an incomplete dissolution even in four hours. In contrast, the complexes formed presented a higher dissolution rate in simulated gastric fluid (SGF pH 1.2), which indicate that these have different ionization characteristics. According to the results, the freeze-dried and kneaded products exhibited higher dissolution rates than the drug alone, in all the mediums.